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11.4B: Interferons - Biology

11.4B: Interferons - Biology


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Learning Objectives

  • Identify interferons and their effects

Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites, or tumor cells. IFNs belong to the large class of glycoproteins known as cytokines. Interferons are named after their ability to “interfere” with viral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages, they increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes, and they increase the ability of uninfected host cells to resist new infection by virus. Certain symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.

About ten distinct IFNs have been identified in mammals; seven of these have been described for humans. They are typically divided among three IFN classes: type I IFN, type II IFN, and type III IFN. IFNs belonging to all IFN classes are very important for fighting viral infections.

Based on the type of receptor through which they signal, human interferons have been classified into three major types:

  • Interferon type I: All type I IFNs bind to a specific cell surface receptor complex, known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.
  • Interferon type II: These bind to IFNGR that consist of IFNGR1 and IFNGR2 chains. In humans this is IFN-γ.
  • Interferon type III: These signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings.

Effects of Interferons

All interferons share several common effects; they are antiviral agents and can fight tumors. As an infected cell dies from a cytolytic virus, viral particles are released that can infect nearby cells. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses. They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. The effect of IFN on p53 is also linked to its protective role against certain cancers. Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells. Interferons can inflame the tongue and cause dysfunction in taste bud cells, restructuring or killing taste buds entirely.

By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes. STATs are a family of transcription factors that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However, each IFN type can also activate unique STATs.

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase-STAT (JAK-STAT) signaling pathway. In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate both STAT1 and STAT2. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9—and moves into the cell nucleus. Inside the nucleus, the ISGF3 complex binds to specific nucleotide sequences called IFN-stimulated response elements (ISREs) in the promoters of certain genes, known as IFN stimulated genes ISGs. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes. Interferome is a curated online database of ISGs (www.interferome.org). Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters. Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. Both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway. Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce gene transcription. Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.

Key Points

  • Interferons are named after their ability to “interfere” with viral replication within host cells.
  • IFNs are divided into three classes: type I IFN, type II IFN, and type III IFNs.
  • IFNs activate immune cells (natural killer cells and macrophages ), increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus.

Key Terms

  • Interferons: Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells. They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.
  • pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
  • immune cells: White blood cells, or leukocytes, are cells of the immune system involved in defending the body against both infectious disease and foreign materials.

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Pfizer buys out Array BioPharma for $11.4 Billion to beef up its oncology offerings

Reporter: Stephen J. Williams, PhD

Three years after purchasing Medivation for $14.3 billion, Pfizer is back with another hefty M&A deal. And once again, it’s betting on oncology.

In the first big M&A deal under new CEO Albert Bourla, Pfizer has agreed to buy oncology specialist Array BioPharma for a total value of about $11.4 billion, the two companies unveiled Monday. The $48-per-share offer represents a premium of about 62% to Array stock’s closing price on Friday.

With the acquisition, Pfizer will beef up its oncology offerings with two marketed drugs, MEK inhibitor Mektovi and BRAF inhibitor Braftovi, which are approved as a combo treatment for melanoma and recently turned up positive results in colon cancer.

The buy will enhance the Pfizer innovative drug business’ “long-term growth trajectory,” Bourla said in a Monday statement, dubbing Mektovi-Braftovi “a potentially industry-leading franchise for colorectal cancer.”

In a recent interim analysis of a trial in BRAF-mutant metastatic colorectal cancer, the pair, used in tandem with Eli Lilly and Merck KGaA’s Erbitux, produced a benefit in 26% of patients, versus the 2% that chemotherapy helped. The combo also showed it could reduce the risk of death by 48%. SVB Leerink analysts at that time called the data “extremely compelling.”

Right now, one in every three new patients with mutated metastatic melanoma is getting the combo, despite its third-to-market behind combos from Roche and Novartis, Andy Schmeltz, Pfizer’s oncology global president, said during an investor briefing on Monday.

It is being studied in more than 30 clinical studies across several solid tumor indications. Moving forward, Pfizer believes the combo could potentially be used in the adjuvant setting to prevent tumor recurrence after surgery, Pfizer’s chief scientific officer, Mikael Dolsten, said on the call. The company is also keen to know how it could be paired up with Pfizer’s own investigational PD-1, he said, as the combo is already in studies with other PD-1/L1s.

But as Pfizer execs have previously said, the company’s current business development strategy no longer centers on adding revenues “now or soon,” but rather on strengthening Pfizer’s pipeline with earlier-stage assets. And Array can help there, too.

“We are very excited by Array’s impressive track record of successfully discovering and developing innovative small-molecules and targeted cancer therapies,” Dolsten said in a statement.

On top of Mektovi and Braftovi, Array has a long list of out-licensed drugs that could generate big royalties over time. For example, Vitrakvi, the first drug to get an initial FDA approval in tumors with a particular molecular feature regardless of their location, was initially licensed to Loxo Oncology—which was itself snapped up by Eli Lilly for $8 billion—but was taken over by pipeline-hungry Bayer. There are other drugs licensed to the likes of AstraZeneca, Roche, Celgene, Ono Pharmaceutical and Seattle Genetics, among others.

Those drugs are also a manifestation of Array’s strong research capabilities. To keep those Array scientists doing what they do best, Pfizer is keeping a 100-person team in Colorado as a standalone research unit alongside Pfizer’s existing hubs, Schmeltz said.

Pfizer is counting on Array to augment its leadership in breast cancer, an area championed by Ibrance, and prostate cancer, the pharma giant markets Astellas-partnered Xtandi. For 2018, revenues from the Pfizer oncology portfolio jumped to $7.20 billion—up from $6.06 billion in 2017—mainly thanks to those two drugs.

About Array BioPharma

Array markets BRAFTOVI ® (encorafenib) capsules in combination with MEKTOVI ® (binimetinib) tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or BRAF V600K mutation in the United States and with partners in other major worldwide markets.* Array’s lead clinical programs, encorafenib and binimetinib, are being investigated in over 30 clinical trials across a number of solid tumor indications, including a Phase 3 trial in BRAF-mutant metastatic colorectal cancer. Array’s pipeline includes several additional programs being advanced by Array or current license-holders, including the following programs currently in registration trials: selumetinib (partnered with AstraZeneca), LOXO-292 (partnered with Eli Lilly), ipatasertib (partnered with Genentech), tucatinib (partnered with Seattle Genetics) and ARRY-797. Vitrakvi ® (larotrectinib, partnered with Bayer AG) is approved in the United States and Ganovo ® (danoprevir, partnered with Roche) is approved in China.

Other Articles of Note of Pfizer Merger and Acquisition deals on this Open Access Journal Include:

From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer A Curation of Deals, Discovery and the State of Pharma

Pfizer Near Allergan Buyout Deal But Will Fed Allow It?

Pfizer offers legal guarantees over AstraZeneca bid

Re-Creation of the Big Pharma Model via Transformational Deals for Accelerating Innovations: Licensing vs In-house inventions


SUMMARY

The present disclosure provides a NaPi2b-targeted antibody-drug conjugate (such as a NaPi2b-targeted antibody-polymer-drug conjugate) that is biodegradable, biocompatible and exhibits high drug load as well as specific binding to the extracellular region of SLC34A2. The NaPi2b-targeted antibody-drug conjugates (e.g., NaPi2b-targeted antibody-polymer-drug conjugates) provided herein include an antibody that specifically recognizes NaPi2b, also known as sodium-dependent phosphate transport protein 2B. The antibodies used in the NaPi2b-targeted antibody-drug conjugates disclosed herein can or may also include those that are capable of and useful for modulating, blocking, inhibiting, reducing, antagonizing, neutralizing or otherwise interfering with at least one biological activity of NaPi2b. Antibodies disclosed herein also include antibodies that bind soluble NaPi2b.

In some embodiments, the NaPi2b-targeted antibody disclosed herein can be connected with an agent to form a conjugate. In some embodiments, the agent is a therapeutic agent. In some embodiments, the agent is an antineoplastic agent. In some embodiments, the agent is a toxin or fragment thereof. In some embodiments, the agent is (a) an auristatin compound (b) a calicheamicin compound (c) a duocarmycin compound (d) SN38, (e) a pyrrolobenzodiazepine (f) a vinca compound (g) a tubulysin compound (h) a non-natural camptothecin compound (i) a maytansinoid compound (j) a DNA binding drug (k) a kinase inhibitor (1) a MEK inhibitor (m) a KSP inhibitor (n) a topoisomerase inhibitor (o) a DNA-alkylating drug (p) a RNA polymerase inhibitor or analogues thereof. In some embodiments, the agent is conjugated to the NaPi2b-targeted antibody via a linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the agent is any of the toxins described herein.

In one aspect, the NaPi2b-targeted antibody conjugate described herein includes an isolated NaPi2b-targeted antibody, connected directly or indirectly to one or more therapeutic or diagnostic agents (“D”). In some embodiments, the NaPi2b-targeted antibody conjugate also includes one or more polymeric scaffolds connected to the antibody, wherein each of the one or more D is independently connected to the antibody via the one or more polymeric scaffolds.

In some embodiments, each of the one or more polymeric scaffolds that are connected to the isolated NaPi2b-targeted antibody, independently, comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF), e.g., PHF having a molecular weight ranging from about 2 kDa to about 40 kDa.

In some embodiments, each of the one or more polymeric scaffolds independently is of Formula (Ic):

L D1 is a carbonyl-containing moiety

is independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect and the

between L D1 and D denotes direct or indirect attachment of D to L D1

is independently a second linker not yet connected to the isolated antibody, in which L P2 is a moiety containing a functional group that is yet to form a covalent bond with a functional group of the isolated antibody and the

between L D1 and L P2 denotes direct or indirect attachment of L P2 to L D1 , and each occurrence of the second linker is distinct from each occurrence of the first linker

is independently a third linker that connects each D-carrying polymeric scaffold to the isolated antibody in which the terminal

attached to L P2 denotes direct or indirect attachment of L P2 to the isolated antibody upon formation of a covalent bond between a functional group of L P2 and a functional group of the isolated antibody and each occurrence of the third linker is distinct from each occurrence of the first linker

m is an integer from 1 to about 300,

m1 is an integer from 1 to about 140,

m2 is an integer from 1 to about 40,

m3 is an integer from 0 to about 18,

m4 is an integer from 1 to about 10

the sum of m, m1, m2, m3, and m4 ranges from about 15 to about 300 and the total number of L P2 connected to the isolated antibody is 10 or less.

The conjugate described herein can include one or more of the following features:

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody has a molecular weight of 40 kDa or greater (e.g., 60 kDa or greater, 80 kDa or greater, 100 kDa or greater, 120 kDa or greater, 140 kDa or greater, 160 kDa or greater, 180 kDa or greater, or 200 kDa or greater, or about 40-200 kDa, 40-180 kDa, 40-140 kDa, 60-200 kDa, 60-180 kDa, 60-140 kDa, 80-200 kDa, 80-180 kDa, 80-140 kDa, 100-200 kDa, 100-180 kDa, 100-140 kDa, or 140-150 kDa). In some embodiments, the isolated NaPi2b-targeted antibody or any antibody of the disclosure, including, by way of non-limiting example, the XMT 1535 antibody and the 10H1.11.4B antibody described herein.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody specifically binds to an epitope of human NaPi2b. In some embodiments, the isolated antibody specifically binds to an epitope on the extracellular domain of human NaPi2b.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody is the XMT 1535 antibody and/or the 10H1.11.4B antibody described herein, as well as biosimilars thereof. Alternatively, the monoclonal antibody is an antibody that binds to the same epitope and/or cross blocks an antibody of the disclosure or biosimilars thereof. These antibodies are respectively referred to herein as “NaPi2b antibodies” or “NaPi2b-targeted antibodies”. NaPi2b antibodies include fully human monoclonal antibodies, as well as humanized monoclonal antibodies and chimeric antibodies. These antibodies show specificity for human NaPi2b, and they can or may modulate, block, inhibit, reduce, antagonize, neutralize or otherwise interfere with at least one NaPi2b activity.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody is a monoclonal antibody.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody is a rabbit, mouse, chimeric, humanized or fully human monoclonal antibody.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody is an IgG isotype. In some embodiments, the isolated NaPi2b-targeted antibody is an IgG1 isotype.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a variable heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) and a variable heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GETARATFAY (SEQ ID NO: 7). For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a variable light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a variable light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a CDRH1 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a CDRH2 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a CDRH3 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GETARATFAY (SEQ ID NO: 7) a CDRL1 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a CDRL2 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a CDRL3 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7). For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a CDRH1 comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a CDRH2 comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a variable CDRH3 comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a CDRL1 comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a CDRL2 comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a CDRL3 comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain (VH) region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 3. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain (VL) region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 4.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a VH region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 3, and a VL region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 4.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain (VH) region comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the antibodies used in the antibody-drug conjugates disclosed herein thereof used in the antibody-drug conjugates disclosed herein include a variable light chain (VL) region comprising the amino acid sequence of SEQ ID NO: 4.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a VH region comprising the amino acid sequence of SEQ ID NO: 3, and a VL region comprising the amino acid sequence of SEQ ID NO: 4.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 1. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a light chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 2.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 1, and a light chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 2.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising the amino acid sequence of SEQ ID NO: 1. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a light chain comprising the amino acid sequence of SEQ ID NO: 2.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and a light chain comprising the amino acid sequence of SEQ ID NO: 2.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain complementarity determining region 1 (CDRH1) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a variable heavy chain complementarity determining region 2 (CDRH2) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) and a variable heavy chain complementarity determining region 3 (CDRH3) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20). For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain complementarity determining region 1 (CDRL1) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a variable light chain complementarity determining region 2 (CDRL2) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a variable light chain complementarity determining region 3 (CDRL3) comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a CDRH1 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20). For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain (VH) region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 16. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain (VL) region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 17.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a VH region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 16, and a VL region comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 17.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable heavy chain (VH) region comprising the amino acid sequence of SEQ ID NO: 16. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a variable light chain (VL) region comprising the amino acid sequence of SEQ ID NO: 17.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a VH region comprising the amino acid sequence of SEQ ID NO: 16, and a VL region comprising the amino acid sequence of SEQ ID NO: 17.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 14. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a light chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 15.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 14, and a light chain comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 15.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising the amino acid sequence of SEQ ID NO: 14. For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a light chain comprising the amino acid sequence of SEQ ID NO: 15.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody includes a heavy chain comprising the amino acid sequence of SEQ ID NO: 14, and a light chain comprising the amino acid sequence of SEQ ID NO: 15.

For example, in Formula (Ic), the isolated NaPi2b-targeted antibody is an isolated antibody that competes for specific binding to human NaPi2b with an isolated antibody that includes (i) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10) or (ii) a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

For example, in Formula (Ic), m1 is an integer from 1 to about 120 (e.g., about 1-90) and/or m3 is an integer from 1 to about 10 (e.g., about 1-8).

For example, when the PHF in Formula (Ic) has a molecular weight ranging from about 6 kDa to about 20 kDa (i.e., the sum of m, m1, m2, m3, and m4 ranging from about 45 to about 150), m2 is an integer from 2 to about 20, m3 is an integer from 0 to about 9, m4 is an integer from 1 to about 10, and/or m1 is an integer from 1 to about 75 (e.g., m1 being about 4-45).

For example, when the PHF in Formula (Ic) has a molecular weight ranging from about 8 kDa to about 15 kDa (i.e., the sum of m, m1, m2, m3, and m4 ranging from about 60 to about 110), m2 is an integer from 2 to about 15, m3 is an integer from 0 to about 7, m4 is an integer from 1 to about 10, and/or m1 is an integer from 1 to about 55 (e.g., m1 being about 4-30).

For example, when the PHF in Formula (Ic) has a molecular weight ranging from about 2 kDa to about 20 kDa (i.e., the sum of m, m1, m2, m3, and m4 ranging from about 15 to about 150), m2 is an integer from 1 to about 20, m3 is an integer from 0 to about 10 (e.g., m3 ranging from 0 to about 9), m4 is an integer from 1 to about 8, and/or m1 is an integer from 1 to about 70, and the total number of L P2 connected to the isolated antibody ranges from about 2 to about 8 (e.g., about 2, 3, 4, 5, 6, 7, or 8).

For example, when the PHF in Formula (Ic) has a molecular weight ranging from about 3 kDa to about 15 kDa (i.e., the sum of m, m1, m2, m3, and m4 ranging from about 20 to about 110), m2 is an integer from 2 to about 15, m3 is an integer from 0 to about 8 (e.g., m3 ranging from 0 to about 7), m4 is an integer from 1 to about 8, and/or m1 is an integer from 2 to about 50, and the total number of L P2 connected to the isolated antibody ranges from about 2 to about 8 (e.g., about 2, 3, 4, 5, 6, 7, or 8).

For example, when the PHF in Formula (Ic) has a molecular weight ranging from about 5 kDa to about 10 kDa, (i.e., the sum of m, m1, m2, m3 and m4 ranges from about 40 to about 75), m2 is an integer from about 2 to about 10 (e.g., m2 being about 3-10), m3 is an integer from 0 to about 5 (e.g., m3 ranging from 0 to about 4), m4 is an integer from 1 to about 8 (e.g., m4 ranging from 1 to about 5), and/or m1 is an integer from about 2 to about 35 (e.g., m1 being about 5-35), and the total number of L P2 connected to the isolated antibody ranges from about 2 to about 8 (e.g., about 2, 3, 4, 5, 6, 7, or 8).

For example, each occurrence of D independently is a therapeutic agent, e.g., having a molecular weight of ≦5 kDa.

For example, each occurrence of D independently is a diagnostic agent or a label.

For example, some occurrences of D independently are therapeutic agents (e.g., having a molecular weight of ≦5 kDa) and the other occurrences of D are diagnostic agents or labels.

For example, each occurrence of D independently is an anti-cancer drug, for example, selected from vinca alkaloids, auristatins, tubulysins, duocarmycins, non-natural camptothecin compounds, maytansinoids, calicheamicin compounds, topoisomerase inhibitors, pyrrolobenzodiazepines, DNA binding drugs, DNA-alkylating drugs, RNA polymerase inhibitors, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogs thereof.

For example, each occurrence of the auristatin compound is auristatin, dolastatin (e.g., dolastatin 10 or dolastatin 15), monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), auristatin F hydroxypropyl amide (AF HPA), monomethylauristatin F hydroxypropyl amide (AF HPA), or auristatin F phenylenediamine (AFP).

For example, each occurrence of the duocarmycin or analog thereof is duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, CC-1065, adozelesin, bizelesin, or carzelesin.

For example, each occurrence of the camptothecin compound is camptothecin, CPT-11 (irinotecan), SN-38, or topotecan.

For example, each occurrence of the pyrrolobenzodiazepine compound is a pyrrolobenzodiazepine monomer, a symmetrical pyrrolobenzodiazepine dimer or an unsymmetrical pyrrolobenzodiazepine dimer.

when not connected to the isolated antibody, independently comprises a terminal group W P , in which each W P independently is:

in which R 1K is a leaving group (e.g., halide or RC(O)O— in which R is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety), R 1A is a sulfur protecting group, and ring A is cycloalkyl or heterocycloalkyl, and R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

For example, each R 1A independently is

in which r is 1 or 2 and each of R s1 , R s2 , and R s3 is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

For example, the functional group of L P2 that is yet to form a covalent bond with a functional group of the isolated antibody (such as a functional group or a reactive moiety on an amino acid residue of the antibody, for example, a functional group on a cysteine residue or a lysine residue of the antibody), is selected from —SR p , —S—S-LG,

and halo, in which LG is a leaving group, R p is H or a sulfur protecting group, and one of Xa and Xb is H and the other is a water-soluble maleimido blocking moiety, or Xa and Xb, together with the carbon atoms to which they are attached for a carbon-carbon double bond. For example, the functional group of L P2 that is yet to form a covalent bond is a functional group that is not reacted with a functional group of the isolated antibody, e.g.,

as the functional group of L P2 , in which one of Xa and Xb is H and the other is a water-soluble maleimido blocking moiety, or Xa and Xb.

For example, L D1 comprises —X—(CH2)v—C(═O)— with X directly connected to the carbonyl group of

in which X is CH2, O, or NH, and v is an integer from 1 to 6.

For example, each occurrence of

is independently —C(═O)—X—(CH2)v—C(═O)—NH—(CH2)u—NH—C(═O)—(CH2)w—(OCH2)x—NHC(═O)—(CH2)y-M, in which X is CH2, O, or NH, each of v, u, w, x and y independently is an integer from 1 to 6, and M is

wherein one of Xa and Xb is H and the other is a water-soluble maleimido blocking moiety, or Xa and Xb, together with the carbon atoms to which they are attached for a carbon-carbon double bond.

For example, each of v, u, w, x and y is 2.

For example, the ratio between D and the isolated NaPi2b-targeted antibody is about 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6 1, 5:1, 4:1, 3:1, 2:1 or 1:1.

For example, the ratio between D and the isolated NaPi2b-targeted antibody is about 20:1, 15:1, 10:1, 5:1, 2:1 or 1:1.

For example, the ratio between D and the isolated NaPi2b-targeted antibody is about 16:1, 15:1, 14:1, 13:1, 12:1, 11:1 or 10:1.

For example, the ratio between D and the isolated NaPi2b-targeted antibody is about 15:1, 14:1, 13:1, 12:1 or 11:1.

For example, the ratio between D and the isolated NaPi2b-targeted antibody is about 15:1, 14:1, 13:1 or 12:1.

For example, the ratio between the D and the isolated NaPi2b-targeted antibody is about 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

For example, each of the one or more D-carrying polymeric scaffolds independently is of Formula (Id):

m3a is an integer from 0 to about 17,

m3b is an integer from 1 to about 8, and

denotes the direct attachment of the one or more polymeric scaffolds to the isolated NaPi2b-targeted antibody having a molecular weight of 40 kDa or greater and (i) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10) or (ii) a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

In some embodiments, the isolated NaPi2b-targeted antibody has a molecular weight of 40 kDa or greater and includes (i) a CDRH1 comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a CDRH2 comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a CDRH3 comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a CDRL1 comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a CDRL2 comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a CDRL3 comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

In some embodiments, the isolated NaPi2b-targeted antibody has a molecular weight of 40 kDa or greater and includes a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

The scaffold of Formula (Id) can include one or more of the following features:

The sum of m3a and m3b is between 1 and 18.

When the PHF in Formula (Id) has a molecular weight ranging from about 2 kDa to about 40 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 15 to about 300, m1 is an integer from 1 to about 140, m2 is an integer from 1 to about 40, m3a is an integer from 0 to about 17, m3b is an integer from 1 to about 8, the sum of m3a and m3b ranges from 1 and about 18, and the ratio between the PHF and the isolated NaPi2b-targeted antibody is 10 or less.

When the PHF in Formula (Id) has a molecular weight ranging from about 2 kDa to about 20 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 15 to about 150, m1 is an integer from 1 to about 70, m2 is an integer from 1 to about 20, m3a is an integer from 0 to about 9, m3b is an integer from 1 to about 8, the sum of m3a and m3b ranges from 1 and about 10, and the ratio between the PHF and the isolated NaPi2b-targeted antibody is an integer from 2 to about 8.

When the PHF in Formula (Id) has a molecular weight ranging from about 3 kDa to about 15 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 20 to about 110, m1 is an integer from 2 to about 50, m2 is an integer from 2 to about 15, m3a is an integer from 0 to about 7, m3b is an integer from 1 to about 8, the sum of m3a and m3b ranges from 1 and about 8 and the ratio between the PHF and the isolated NaPi2b-targeted antibody is an integer from 2 to about 8 (e.g., from about 2 to about 6 or from about 2 to about 4).

When the PHF in Formula (Id) has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 40 to about 75, m1 is an integer from about 2 to about 35, m2 is an integer from about 2 to about 10, m3a is an integer from 0 to about 4, m3b is an integer from 1 to about 5, the sum of m3a and m3b ranges from 1 and about 5 and the ratio between the PHF and the isolated NaPi2b-targeted antibody is an integer from 2 to about 8 (e.g., from about 2 to about 6 or from about 2 to about 4).

In certain embodiments, the ratio between auristatin F hydroxypropyl amide (“AF HPA”) and the isolated NaPi2b-targeted antibody can be about 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In certain embodiments, the ratio between AF HPA and the isolated NaPi2b-targeted antibody can be about 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In other embodiments, the ratio between AF HPA and the isolated NaPi2b-targeted antibody can be about 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In some embodiments, the ratio between AF HPA and isolated NaPi2b-targeted antibody can be about 16:1, 15:1, 14:1, 13:1, 12:1, 11:1 or 10:1.

In some embodiments, the ratio between AF HPA and isolated NaPi2b-targeted antibody can be about 15:1, 14:1, 13:1, 12:1 or 11:1.

In some embodiments, the ratio between AF HPA and isolated NaPi2b-targeted antibody can be about 15:1, 14:1, 13:1 or 12:1.

In certain embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

In certain embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

In other embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

In other embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 6:1, 5:1, 4:1, 3:1 or 2:1.

In other embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 6:1, 5:1, 4:1 or 3:1.

In some embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 5:1, 4:1 or 3:1.

In some embodiments, the ratio between PHF and isolated NaPi2b-targeted antibody can be about 4:1, 3:1 or 2:1.

The water-soluble maleimido blocking moieties (e.g., Xa or Xb) are moieties that can be covalently attached to one of the two olefin carbon atoms upon reaction of the maleimido group with a thiol-containing compound of Formula (II):

R90 is NHR91, OH, COOR93, CH(NHR91)COOR93 or a substituted phenyl group

R93 is hydrogen or C1-4 alkyl

d is an integer from 1 to 3.

In one embodiment, the water-soluble maleimido blocking compound of Formula (II) can be cysteine, N-acetyl cysteine, cysteine methyl ester, N-methyl cysteine, 2-mercaptoethanol, 3-mercaptopropanoic acid, 2-mercaptoacetic acid, mercaptomethanol (i.e., HOCH2SH), benzyl thiol in which phenyl is substituted with one or more hydrophilic substituents, or 3-aminopropane-1-thiol. The one or more hydrophilic substituents on phenyl comprise OH, SH, methoxy, ethoxy, COOH, CHO, COC1-4 alkyl, NH2, F, cyano, SO3H, PO3H, and the like.

In another aspect, the water-soluble maleimido blocking group is —S—(CH2)d—R90, in which,

R91 is hydrogen or CH3CO and

In another embodiment, the water-soluble maleimido blocking group is —S—CH2—CH(NH2)COOH.

In certain embodiments, the conjugate described herein comprises one or more D-carrying PHF, each of which independently is of Formula (If), wherein the PHF has a molecular weight ranging from about 2 kDa to about 40 kDa:

m is an integer from 1 to about 300,

m1 is an integer from 1 to about 140,

m2 is an integer from 1 to about 40,

m3a is an integer from 0 to about 17,

m3b is an integer from 1 to about 8

the sum of m3a and m3b ranges from 1 and about 18

the sum of m, m1, m2, m3a, and m3b ranges from about 15 to about 300

denotes the attachment of one or more PHF polymeric scaffolds to the isolated antibody that specifically binds to SLC34A2, wherein the isolated antibody that specifically binds to SLC34A2 is an isolated antibody that comprises (i) a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10) or (ii) a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23) and

the ratio between the PHF and the antibody is 10 or less.

In some embodiments, the isolated NaPi2b-targeted antibody specifically binds to SLC34A2 and includes (i) a CDRH1 comprising the amino acid sequence GYTFTGYNIH (SEQ ID NO: 5) a CDRH2 comprising the amino acid sequence AIYPGNGDTSYKQKFRG (SEQ ID NO: 6) a CDRH3 comprising the amino acid sequence GETARATFAY (SEQ ID NO: 7) a CDRL1 comprising the amino acid sequence SASQDIGNFLN (SEQ ID NO: 8) a CDRL2 comprising the amino acid sequence YTSSLYS (SEQ ID NO: 9) and a CDRL3 comprising the amino acid sequence QQYSKLPLT (SEQ ID NO: 10).

In some embodiments, the isolated NaPi2b-targeted antibody specifically binds to SLC34A2 and includes a CDRH1 comprising the amino acid sequence GFSFSDFAMS (SEQ ID NO: 18) a CDRH2 comprising the amino acid sequence ATIGRVAFHTYYPDSMKG (SEQ ID NO: 19) a CDRH3 comprising the amino acid sequence ARHRGFDVGHFDF (SEQ ID NO: 20) a CDRL1 comprising the amino acid sequence RSSETLVHSSGNTYLE (SEQ ID NO: 21) a CDRL2 comprising the amino acid sequence RVSNRFS (SEQ ID NO: 22) and a CDRL3 comprising the amino acid sequence FQGSFNPLT (SEQ ID NO: 23).

The scaffold of Formula (If) can include one or more of the following features:

When the PHF in Formula (If) has a molecular weight ranging from about 2 kDa to about 20 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 15 to about 150, m1 is an integer from 1 to about 70, m2 is an integer from 1 to about 20, m3a is an integer from 0 to about 9, m3b is an integer from 1 to about 8, the sum of m3a and m3b ranges from 1 and about 10, and the ratio between the PHF and the antibody is an integer from 2 to about 8.

When the PHF in Formula (If) has a molecular weight ranging from about 3 kDa to about 15 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 20 to about 110, m1 is an integer from 2 to about 50, m2 is an integer from 2 to about 15, m3a is an integer from 0 to about 7, m3b is an integer from 1 to about 8, the sum of m3a and m3b ranges from 1 and about 8 and the ratio between the PHF and the antibody is an integer from 2 to about 8 (e.g., from about 2 to about 6 or from about 2 to about 4).

When the PHF in Formula (If) has a molecular weight ranging from about 5 kDa to about 10 kDa, the sum of m, m1, m2, m3a and m3b ranges from about 40 to about 75, m1 is an integer from about 2 to about 35, m2 is an integer from about 2 to about 10, m3a is an integer from 0 to about 4, m3b is an integer from 1 to about 5, the sum of m3a and m3b ranges from 1 and about 5 and the ratio between the PHF and the antibody is an integer from 2 to about 8 (e.g., from about 2 to about 6 or from about 2 to about 4).

In certain embodiments, the ratio between auristatin F hydroxypropyl amide (“AF HPA”) and the antibody can be about 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In certain embodiments, the ratio between AF HPA and the antibody can be about 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In other embodiments, the ratio between AF HPA and the antibody can be about 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1 or 6:1.

In some embodiments, the ratio between AF HPA and the antibody can be about 16:1, 15:1, 14:1, 13:1, 12:1, 11:1 or 10:1.

In some embodiments, the ratio between AF and the antibody can be about 15:1, 14:1, 13:1, 12:1 or 11:1.

In some embodiments, the ratio between AF HPA and the antibody can be about 15:1, 14:1, 13:1 or 12:1.

In certain embodiments, the ratio between PHF and the antibody can be about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

In certain embodiments, the ratio between PHF and the antibody can be about 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.

In other embodiments, the ratio between PHF and the antibody can be about 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.

In other embodiments, the ratio between PHF and the antibody can be about 6:1, 5:1, 4:1, 3:1 or 2:1.

In other embodiments, the ratio between PHF and the antibody can be about 6:1, 5:1, 4:1 or 3:1.

In some embodiments, the ratio between PHF and the antibody can be about 5:1, 4:1 or 3:1.

In some embodiments, the ratio between PHF and the antibody can be about 4:1, 3:1 or 2:1.

Another aspect of the disclosure features a method of preparing a conjugate described herein. The method includes reacting the isolated antibody with a D-carrying polymeric scaffold of Formula (Ia) such that the conjugate is formed:

L D1 is a carbonyl-containing moiety

is independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect and the

between L D1 and D denotes direct or indirect attachment of D to L D1

is independently a second linker not yet connected to the isolated antibody, in which L P2 is a moiety containing a functional group that is yet to form a covalent bond with a functional group of the isolated antibody, and the

between L D1 and L P2 denotes direct or indirect attachment of L P2 to L D1 , and each occurrence of the second linker is distinct from each occurrence of the first linker

m is an integer from 1 to about 300,

m1 is an integer from 1 to about 140,

m2 is an integer from 1 to about 40,

m3 is an integer from 1 to about 18, and

the sum of m, m1, m2 and m3 ranges from about 15 to about 300.

In the formulae for polymeric scaffolds disclosed herein, the disconnection or gap between the polyacetal units indicates that the units can be connected to each other in any order. In other words, the appending groups that contain, e.g., D, L P2 , and the isolated antibody, can be randomly distributed along the polymer backbone.

The present disclosure also provides methods of treating, preventing, delaying the progression of or otherwise ameliorating a symptom of one or more pathologies associated with aberrant NaPi2b expression, function and/or activation or alleviating a symptom associated with such pathologies, by administering a conjugate disclosed herein to a subject in which such treatment or prevention is desired. The subject to be treated is, e.g., human. The conjugate are administered in an amount sufficient to treat, prevent or alleviate a symptom associated with the pathology.

The present disclosure also provides methods of treating, preventing, delaying the progression of or otherwise ameliorating a symptom of one or more pathologies associated with NaPi2b expression, function and/or activation or alleviating a symptom associated with such pathologies, by administering a conjugate disclosed herein to a subject in which such treatment or prevention is desired. The subject to be treated is, e.g., human. The conjugate is administered in an amount sufficient to treat, prevent or alleviate a symptom associated with the pathology.

Pathologies treated and/or prevented using the conjugates disclosed herein including, for example, a cancer. In some embodiments, the conjugates disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a NaPi2b expressing cancer. For example, the conjugates disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of a cancer selected from the group consisting of ovarian cancer (such as epithelial ovarian cancer), thyroid cancer, colorectal cancer, lung cancer, non-small cell lung cancer (NSCLC) such as non-squamous NSCLC, breast cancer, kidney cancer and salivary duct carcinoma.

In some embodiments, the conjugates disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer.

In some embodiments, the conjugates disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC.

In some embodiments, the conjugates disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer.

The disclosure also provides kits and/or methods for identifying or otherwise refining, e.g., stratifying, a patient population suitable for therapeutic administration of a NaPi2b-targeted antibody-drug conjugates disclosed herein by identifying the NaPi2b score of subject prior to treatment with a NaPi2b-targeted antibody-drug conjugate disclosed herein. In some embodiments, the subject is identified as having a scoring of 1+ or 2+ or 3+ for NaPi2b expression. In some embodiments, the test cell population is derived from fresh, unfrozen tissue from a biopsy sample. In some embodiments, the test cell population is derived from a primary or metastatic site. In some embodiments, the test cell population is derived from a frozen tissue from a biopsy or surgical sample or ascetic fluid or pleural fluid. In some embodiments, the test cell population is derived from a fixed tissue (e.g., formalin fixation) from a biopsy or surgical sample.

The IHC test measures the amount of NaPi2b receptor protein on the surface of cells in a cancer tissue sample, e.g., an ovarian cancer tissue sample or a lung cancer sample, and assigns the detected level of cell surface NaPi2b receptor NaPi2b score of 0, 1+, 2+ or 3+.

In some embodiments, the subject is refractory to chemotherapy, including standard, front-line chemotherapeutic agents.

In some embodiments, the subject has platinum-resistant ovarian cancer.

In some embodiments, the subject has platinum-sensitive ovarian cancer.

In some embodiments, the subject has platinum-refractory ovarian cancer.

In some embodiments, the subject has advanced ovarian cancer and has not received any prior therapy for treating cancer (e.g., ovarian cancer). In some embodiments, the subject has advanced ovarian cancer and has not received any prior chemotherapy for treating cancer (e.g., ovarian cancer).

The NaPi2b-targeted antibody-drug conjugates used in any of the embodiments of the methods and uses provided herein can be administered at any stage of the disease. For example, such a NaPi2b-targeted antibody-drug conjugate can be administered to a patient suffering cancer of any stage, from early to metastatic.

In some embodiments, the NaPi2b-targeted antibody-drug conjugates of the disclosure can be administered either alone or in combination with other compositions in a therapy. For instance, a conjugate of the disclosure may be co-administered with at least one additional therapeutic agent and/or adjuvant. In certain embodiments, the additional therapeutic agent is a small molecule inhibitor, another antibody-based therapy, a polypeptide or peptide-based therapy, a nucleic acid-based therapy and/or other biologic. The additional therapeutic agent can either be the same as the “D” used to form the conjugate or different.

In certain embodiments, the additional therapeutic agent is a cytotoxic agent, a chemotherapeutic agent, a growth inhibitory agent, an angiogenesis inhibitor, a PARP (poly(ADP)-ribose polymerase) inhibitor, an alkylating agent, an anti-metabolite, an anti-microtubule agent, a topoisomerase inhibitor, a cytotoxic antibiotic, any other nucleic acid damaging agent or an immune checkpoint inhibitor. In one embodiment, the therapeutic agent used in the treatment of cancer, includes but is not limited to, a platinum compound (e.g., cisplatin or carboplatin) a taxane (e.g., paclitaxel or docetaxel) a topoisomerase inhibitor (e.g., irinotecan or topotecan) an anthracycline (e.g., doxorubicin (ADRIAMYCIN®) or liposomal doxorubicin (DOXIL®)) an anti-metabolite (e.g., gemcitabine, pemetrexed) cyclophosphamide vinorelbine (NAVELBINE®) hexamethylmelamine ifosfamide etoposide an angiogenesis inhibitor (e.g., Bevacizumab (Avastin®)), thalidomide, TNP-470, platelet factor 4, interferon or endostatin) a PARP inhibitor (e.g., Olaparib (Lynparza™)) an immune checkpoint inhibitor, such as for example, a monoclonal antibody that targets either PD-1 or PD-L ((e.g., pembrolizumab (Keytruda®), atezolizumab (MPDL3280A) or nivolumab (Opdivo®)) or CTLA-4 (e.g., Ipilimumab (Yervoy®)), a kinase inhibitor (e.g., sorafenib or erlotinib), an ALK inhibitor (e.g. crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), dalantercept (ACE-041), brigatinib (AP26113), entrectinib (NMS-E628), PF-06463922 TSR-011, CEP-37440 and X-396), a proteasome inhibitor (e.g., bortezomib or carfilzomib), an immune modulating agent (e.g., lenalidomide or IL-2), a radiation agent, and/or a biosimilar thereof and/or combinations thereof. Other suitable agents include an agent considered standard of care by those skilled in the art and/or a chemotherapeutic agent well known to those skilled in the art.

In some embodiments, the immune checkpoint inhibitor suitable for the combinations and methods of the disclosure is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.

In some embodiments, the immune checkpoint inhibitors inhibits a checkpoint protein that comprises CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD226, CD276, DR3, GITR, HAVCR2, HVEM, IDO1, IDO2, ICOS (inducible T cell costimulator), LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), OX-40, SLAM, TIGHT, VTCN1 or a combination thereof.

In some embodiments, the immune checkpoint inhibitor interacts with a ligand of a checkpoint protein that comprises CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD226, CD276, DR3, GITR, HAVCR2, HVEM, IDO1, IDO2, ICOS (inducible T cell costimulator), LAIR1, LIGHT, MARCO (macrophage receptor with collagenous structure), OX-40, SLAM, TIGHT, VTCN1 or a combination thereof.

In some embodiments, the immune checkpoint inhibitor inhibits a checkpoint protein that comprises CTLA-4, PDL1, PD1 or a combination thereof.

In some embodiments, the immune checkpoint inhibitor comprises pembrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1 105, durvalumab (MEDI4736), MPDL3280A, BMS-936559, IPH2101, TSR-042, TSR-022, ipilimumab, lirilumab, atezolizumab, avelumab, tremelimumab, or a combination thereof.

In some embodiments, the immune checkpoint inhibitor comprises nivolumab (BMS-936558), ipilimumab, pembrolizumab, atezolizumab, tremelimumab, durvalumab, avelumab, or a combination thereof.

In some embodiments, the NaPi2b-targeted antibody-drug conjugate and additional agent(s) are formulated into a single therapeutic composition, and the NaPi2b-targeted antibody-drug conjugate and additional agent are administered simultaneously. Alternatively, the NaPi2b-targeted antibody-drug conjugate and additional agent are separate from each other, e.g., each is formulated into a separate therapeutic composition, and the NaPi2b-targeted antibody-drug conjugate and the additional agent are administered simultaneously, or the NaPi2b-targeted antibody-drug conjugates and the additional agent are administered at different times during a treatment regimen. For example, the NaPi2b-targeted antibody-drug conjugate is administered prior to the administration of the additional agent, the NaPi2b-targeted antibody-drug conjugate is administered subsequent to the administration of the additional agent, or the NaPi2b-targeted antibody-drug conjugate and the additional agent are administered in an alternating fashion. As described herein, the NaPi2b-targeted antibody-drug conjugate antibody and additional agent are administered in single doses or in multiple doses.

In some embodiments, the NaPi2b-targeted antibody-drug conjugate and the immune checkpoint inhibitor are formulated in the same formulation.

In some embodiments, the NaPi2b-targeted antibody-drug conjugate and the immune checkpoint inhibitor are formulated in separate formulations.

In some embodiments, the combination comprising a NaPi2b-targeted antibody-drug conjugate and an immune checkpoint inhibitor disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer.

In some embodiments, the combination comprising a NaPi2b-targeted antibody-drug conjugate and an immune checkpoint inhibitor disclosed herein are useful in treating, preventing, delaying the progression of or otherwise ameliorating a symptom of NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC.

Also disclosed are kits comprising a NaPi2b-targeted antibody-drug conjugate and an immune checkpoint inhibitor. The kit components may be packaged together or separated into two or more containers. In some embodiments, the containers may be vials that contain sterile, lyophilized formulations of a composition that are suitable for reconstitution. A kit may also contain one or more buffers suitable for reconstitution and/or dilution of other reagents. Other containers that may be used include, but are not limited to, a pouch, tray, box, tube, or the like. Kit components may be packaged and maintained sterilely within the containers. Another component that can be included is instructions to a person using a kit for its use.

Pharmaceutical compositions according to the disclosure can include a NaPi2b-targeted antibody-drug conjugate disclosed herein and a suitable carrier. These pharmaceutical compositions can be included in kits, such as, for example, diagnostic kits.

One skilled in the art will appreciate that the antibodies disclosed herein have a variety of uses. For example, the proteins disclosed herein are used as therapeutic agents. The antibodies disclosed herein are also used as reagents in diagnostic kits or as diagnostic tools, or these antibodies can be used in competition assays to generate therapeutic reagents.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and claims.