Treatment of cancer using b7-h4-targeted antibody-drug conjugates

Abstract

Disclosed herein are methods of treatment and dosing regimens for a B7-H4-targeted antibody-drug conjugates for treating cancer.

Description

Attorney Docket No.43704-02721 MRSN-047 / 001WO TREATMENT OF CANCER USING B7-H4-TARGETED ANTIBODY-DRUG CONJUGATESRELATED APPLICATIONS

[0001] This application claims the priority to, and benefit of, U. S. Provisional Application No. 63 / 743,379, filed on January 9, 2025, and U. S. Provisional Application No. 63 / 792,135, filed on April 21, 2025, the contents of each of which are incorporated by reference in their entireties.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The Sequence Listing XML associated with this application is provided electronically in xml file format and is hereby incorporated by reference into the specification. The name of the xml file containing the Sequence Listing is MRSN_047_001 WO_SeqList_ST26.xml. The xml file is 18,841 bytes, created on January 4, 2026, and is being submitted electronically via USPTO Patent Center.FIELD OF THE INVENTION

[0003] This disclosure relates generally to treatment of cancers with B7-H4-targeted antibody-drug conjugates and dosing regimens for administering B7-H4-targeted antibody-drug conjugates for the treatment of cancer.BACKGROUND

[0004] B7-H4, also known as B7-H4, B7x, B7S1, B7-S1, and VTCN1, is a Type I transmembrane protein and is a member of the B7 superfamily of proteins that provides a co-signal in conjunction with a T-cell receptor antigenic signal. B7-H4 is a negative regulator of T-cell function and ligation of T-cells inhibits their growth, cytokine secretion and cytotoxicity. Elimination of B7-H4 in mice does not affect immune cell homeostasis and shows no signs of autoimmunity. The receptor for B7-H4 is unknown and unidentified.

[0005] Human B7-H4 has been mapped on chromosome 1 and is comprised of six exons and five introns spanning 66 kb, of which exon 6 is used for alternative splicing to generate two different transcripts. It is a 282 amino acid protein (including the amino-terminal signal sequence), of which -227 amino acids are predicted to be in the extracellular space following cleavage of the aniino-Attorney Docket No. 43704-02721 MRSN-047 / 001WO terminal signal sequence. B7-H4 comprises an Ig-like V-domain, an Ig- like C domain, a transmembrane domain and a short cytoplasmic tail.

[0006] While B7-H4 expression in healthy tissues is relatively limited at the protein level, B7-H4 is consistently overexpressed in several solid tumors such as gynecological carcinomas of the breast, ovary, and endometrium. Expression of B7-H4 in tumors tends to correlate with poor prognosis. The receptor for B7-H4 is unknown, but it is believed to be expressed on T cells. B7-H4 is believed to directly inhibit T cell activity.

[0007] A wide variety of therapeutic modalities are available for the treatment of advanced cancers including radiotherapy, conventional chemotherapy with cytotoxic antitumor agents, hormone therapy (aromatase inhibitors, luteinizing-hormone releasing-hormone analogues), bisphosphonates and signal -transduction inhibitors. Unfortunately, however, many patients either respond poorly or not at all to any of these therapeutic modalities. Thus, there is a need to identify new therapeutic agents that target the biological activities of B7-H4 and to identify safe and effective methods of administering such therapeutic agents to patients in need thereof.SUMMARY OF THE INVENTION

[0008] The disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a B7-H4-targeted antibody-drug conjugate of Formula (1):Attorney Docket No.43704-02721 MRSN-047 / 001WOwherein i. dis is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRE1 ) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc;is Fuc; and > is GalNAc; and wherein the subject (a) has not received a vascular endothelial growth factor (VEGF)- targeted therapy; (b) does not have or has a prior history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy;and / or (c) has a urineAttorney Docket No. 43704-02721 MRSN-047 / 001WO protein concentration of less than or equal to 500 mg within 14 days prior to administration of the B7-H4-targeted antibody-drug conjugate

[0009] In some embodiments, the VEGF-targeted therapy comprises bevacizumab, pegaptanib, ranibizumab, aflibercept, conbercept, brolucizumab or faricimab.

[0010] The disclosure provides a method of treating cancer in a subject m need thereof, comprising administering to the subject an angiotensin converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB), and a B7-H4-targeted antibody-drug conjugate of Formula (I):(I)wherein i. dis is about 2; li. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRFI1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARD DYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chainAttorney Docket No.43704-02721 MRSN-047 / 001WO complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), lii. the Drug is attached to a heavy chain of the antibody via a l inker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc;is Fuc; and I— I is GalNAc.[001 Ij In some embodiments, the ACE inhibitor and / or ARB is titrated to normal blood pressure.

[0012] In some embodiments, the method further comprising administering the subject a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

[0013] The disclosure provides a method of treating cancer in a subject, comprising administering to the subject a sodium-glucose co-transporter 2 (SGLT2) inhibitor; and a B7-H4-targeted antibody-drug conjugate of Formula (1):wherein i. di3 is about 2; li. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2)Attorney Docket No. 43704-02721 MRSN-047 / 001WO comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), lii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and O is GalNAc.

[0014] The disclosure provides a method of decreasing the incidence or severity of proteinuria m a subject having cancer and receiving a B7-H4-targeted antibody-drug conjugate. comprising administering (a) an ACE inhibitor and / or an ARB and / or (b) a SGLT2 inhibitor; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I)wherein i. dis is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNYAttorney Docket No.43704-02721 MRSN-047 / 001WO (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl ) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and > is GalNAc.

[0015] In some embodiments, the ACE inhibitor and / or ARB is titrated to normal blood pressure.In some embodiments, the SGLT2 inhibitor is dapagliflozin or empagliflozin.In some embodiments, the ARB is azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan or valsartan. In some embodiments, losartan is administered at a dosage of about 25 mg to about 100 mg once daily. In some embodiments, the losartan is administered at a dosage of about 25 mg once daily.In some embodiments, the administration of the ARB and / or the ACE inhibitor is initiated prior to or at the same time as the first administration of the B7-H4-targeted antibody-drug conjugate.In some embodiments, the admistration of ARB and or the ACE inhibitor is continued throughout the period of treatment with the B7-H4-targeted antibody-drug conjugate.In some embodiments, the ACE inhibitor is benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.In some embodiments, the method futher comprising treating the subject with a SGLT2 inhibitor if the subject develops proteinuria during treatment.

[0016] In some embodiments, the antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0017] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the ammo acid sequence of SEQ ID NO: 12.

[0018] In some embodiments, the B7-H4-targeted antibody-drug conjugate is administered by infusion at a dose of between about 28,7 mg / m2to about 115.0 mg / m2.

[0019] In some embodiments, the B7-H4-targeted antibody-drug conjugate is administered at a dose of: about 28.2 mg / m2to about 29.2 mg / m2, about 32.9 mg / m2to about 33.9 mg / m2, about 37.6 mg / m2to about 38.6 mg / m2, about 44.0 mg / m2to about 45.0 mg / m2, about 50.2 mg / m2to about 51.2 mg / m2, about 58.5 mg / m2to about 59.5 mg / m2, about 66.9 mg / m2to about 67.9 mg / m2, about 77.0 mg / m2to about 78.0 mg / m2, about 79.5 mg / m2to about 80.5 mg / m2, about 87.1 mg / m2to about 88.1 mg / m2, about 94.5 mg / m2to about 95.5 mg / m2, or about 114.5 mg / m2to about 115.5 mg / m2.

[0020] In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 28.7 mg / m2. In some embodiments, the B7-H4-targeted antibody¬ drug conjugate dose is administered at a dose of about 33.4 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 38.1 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 44.5 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 50.7 mg / m2. In some embodiments, the B7-H4-targeted antibody¬ drug conjugate dose is administered at a dose of about 59.0 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 67.4 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 77.5 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 80.0 mg / m2. In some embodiments, the B7-H4-targeted antibodydrug conjugate dose is administered at a dose of about 87.6 mg / m2In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 95.0 mg / m2. In some embodiments, the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 115.0 mg / m2

[0021] In some embodiments, if the subject’s body surface area is calculated to be greater than 2.0 m2, the subject is administered a dose calculated based on a body surface area of about 2,0Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0022] In some embodiments, the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 3 weeks thereafter. In some embodiments, the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 4 weeks thereafter. In some embodiments, the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 5 weeks thereafter. In some embodiments, the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 6 weeks thereafter.

[0023] In some embodiments, the dose of the B7-H4-targeted antibody-drug conjugate is administered on day 1 and is administered on day 8 of a treatment cycle, optionally wherein the cycle is a 4-week treatment cycle (e.g., is administered on a dl d8 q2w4 dosing schedule).

[0024] In some embodiments, the cancer is B7-H4-positive, optionally as measured by tumor proportion score (TPS). In some embodiments, the TPS is greater than or equal to 50%. In some embodiments, the TPS is greater than or equal to 70%.

[0025] In some embodiments, the cancer is adenoid cystic carcinoma (ACC), breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HER2 negative breast cancer, for example, is triple negative breast cancer (TNBC) or hormone receptor positive / HER2 negative (HR+ / HER2-) breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is ovarian cancer.

[0026] In some embodiments, the cancer is ACC. In some embodiments, the ACC is ACC Type I. In some embodiments, the ACC is ACC Type II.

[0027] In some embodiments, the subject with ACC is identified for treatment by (a) identification of an activating mutation a Notch pathway gene (e.g., NOTCH-1, NOTCH-2, NOTCH-3, or NOTCH-4), optionally in the NOTCH- 1 gene, optionally as identified by next¬ generation sequencing (NGS); and / or (b) a tumor biopsy testing positive for c-MYC and / or negative or low-expressing for TP63, optionally as measured by immunohistochemistry (IHC).

[0028] In some embodiments, the subject with ACC is identified for treatment by having a clinical course characterized by <3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with atypical sites of metastases (e.g. bone, CNS, and non-pulmonary or -hepatic viscera) and a solid tumor morphology on histologic evaluation.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0029] In some embodiments, the subject that has TNBC has received at least 1 line of systemic therapy in a locally advanced or metastatic breast cancer setting.

[0030] In some embodiments, the subject that has TNBC has received at least 2 lines of systemic therapy in a locally advanced or metastatic breast cancer setting,

[0031] In some embodiments, the subject that has HR+ / HER2- breast cancer has received at least one line of systemic therapy which must have included CDK 4 / 6 inhibitor and endocrine therapy (ET), m an advanced or metastatic breast cancer setting.

[0032] In some embodiments, the subject that has endometrial cancer has received at least I line of systemic therapy including platinum-based chemotherapy for advanced or metastatic disease.

[0033] In some embodiments, the subject that has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer has received at least 1 line of systemic therapy for advanced or metastatic disease including platinum-based chemotherapy.

[0034] In some embodiments, the subject that has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer has received at least 2 lines of systemic therapy for advanced or metastatic disease including platinum-based chemotherapy.

[0035] In some embodiments, the subject is human.

[0036] In some embodiments, the B7-H4-targeted antibody drug conjugate is administered in combination with an immune checkpoint inhibitor molecule, optionally wherein the immune checkpoint inhibitor molecule is a PD-l-binding molecule, e.g., an anti-PD-1 antibody, or a PD-L1- binding molecule, e.g., an anti-PD-Ll antibody.

[0037] In some embodiments, the B7-H4-targeted antibody drug conjugate and the immune checkpoint inhibitor molecule are administered concurrently or sequentially.

[0038] In some embodiments, the B7-H4-targeted antibody drug conjugate is administered to a subject who has received prior therapy comprising a topoisomerase 1 inhibitor-containing antibody drug conjugate.

[0039] In some embodiments, the cancer has become resistant to or not responsive to therapy with the topoisomerase 1 inhibitor-containing antibody drug conjugate (optionally wherein the resistance is caused by resistance to the topoisomerase 1 inhibitor). In some embodiments, the cancer has progressed following therapy with the topoisomerase 1 inhibitor-containing antibody drug conjugate but prior to administration of the B7-H4-targeted antibody drug conjugate.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0040] The disclosure provides a B7-H4-targeted antibody drug conjugate for use in combination with an ACE inhibitor and / or an ARB for the treatment of cancer in a subject; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I)wherein i, di3 is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), hi. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and > is GalNAc.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0041] The disclosure provides a B7-H4-targeted antibody drug conjugate for use in combination with a SGLT2 inhibitor for the treatment of cancer in a subject; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I)wherein i, di3 is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), hi. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and > is GalNAc.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0042] The disclosure provides an ACE inhibitor and / or an ARB, for use in combination with a B7-H4-targeted antibody-drug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated with a B7-H4-targeted antibody-drug conjugate; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):

[0043] wherein i. di3 is about 2; li, the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), hi. the Drug is attached to a heavy chainAttorney Docket No.43704-02721 MRSN-047 / 001WO of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; A is Fuc; and > is GalNAc,

[0044] The disclosure provides an SGLT2 inhibitor, for use in combination with a B7-H4-targeted antibody-drug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated with a B7-H4-targeted antibody-drug conjugate; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):Ji f O OMe O OMe i T O i(I)wherein i. dis is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRIIl) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRII2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQAttorney Docket No.43704-02721 MRSN-047 / 001WO ID NO: 6), and a variable light chain complementarity' determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and ▷ is GalNAc.

[0045] In some embodiments, the B7-H4-targeted antibody drug conjugate is emiltatug ledadotin.

[0046] In some embodiments, the ACE inhibitor, ARB and / or SGLT2 inhibitor reduce or prevent proteinuria in said subject.

[0047] In some embodiments, the B7-H4-targeted antibody-drug conjugate is any B7-H4-targeted antibody-drug conjugate of the disclosure.

[0048] The disclosure provides a kit comprising: (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor, wherein the B7-H4-targeted antibody-drug conjugate is any B7-H4-targeted antibody-drug conjugate of the disclosure.

[0049] The disclosure provides a pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an ACE inhibitor and / or an ARB, for use in combination, wherein the B7-H4-targeted antibody-drug conjugate is any B7-H4-targeted antibody-drug conjugate of the disclosure.

[0050] The disclosure provides a pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an SGLT2 inhibitor for use in combination, wherein the B7-H4-targeted antibody-drug conjugate is any B7-H4-targeted antibody-drug conjugate of the disclosure.

[0051] The disclosure provides a pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor for use m combination, wherein the B7-H4-targeted antibody-drug conjugate is any B7-H4-targeted antibody-drug conjugate of the discl osure.

[0052] Other features and advantages of the invention will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF THE FIGURES

[0053] FIG. 1 is a graph showing the anti-tumor efficacy of a B7-H4-targeted antibody-drug conjugate (XMT-1660) (4.68 / 0.150 mg / kg) and rituximab isotype control conjugate (4.60 / 0.150Attorney Docket No.43704-02721 MRSN-047 / 001WO mg / kg) (all doses are given by antibody / payload) in a patient derived endometrial cancer xenograft mouse model.

[0054] FIG. 2 is a graph showing the anti-tumor efficacy of a B7-H4-targeted antibody-drug conjugate (XMT-1660) (4.61 / 0.150 mg / kg) and palivizumab isotype control (4.54 / 0.150 mg / kg) (all doses are given by antibody / payload) in a patient derived ovarian cancer xenograft mouse model.

[0055] FIG. 3 is a graph showing the anti-tumor efficacy of a B7-H4-targeted antibody-drug conjugate (XMT-1660) (2.30 / 0.075 or 4.60 / 0.150 mg / kg, DAR 5.96) and palivizumab isotype control ADC (2.27 / 0.075 or 4.54 / 0.150 mg / kg, DAR 5.97) (all doses are given by antibody / payload) in a CTG-1692 patient derived ovarian cancer model.

[0056] FIG. 4 is a graph showing the anti-tumor efficacy of palivizumab isotype control conjugate (1.51 / 0.050 or 4.54 / 0.150 mg / kg), a B7-H4-targeted antibody-drug conjugate (XMT-1660) (1.53 / 0.050 or 4.60 / 0.150 mg / kg), anti-PD-1 (10.0 / 0 mg / kg), and XMT-1660 + anti-PD-1 (1.53 / 0.050 mg / kg + 10.0 / 0 mg / kg) (all doses are given by antibody / payload) in a mBR9013 syngeneic breast cancer mouse model.

[0057] FIG. 5 is a schematic representation of the three-component pharmacokinetic model.

[0058] FIG. 6 is a schematic representation of a sequential PK-efficacy model.

[0059] FIG. 7 is a graph showing the mean anti -tumor efficacy of XMT-1660 in a MX-1 mouse xenograft model following administration of XMT-1660 at the indicated doses and dose regimens. Plotted is Mean Tumor (MX-1) Volume. Doses are provided in mg / kg by payload and dose regimens are shown in the legend. After approximately Day 23, curves from G2, G3, G4 and G5 are roughly equivalent, with tumor volume ~ 0.

[0060] FIG. 8 is a graph of the mean (+ / - SD) plasma concentration vs. time (nominal) of conjugated XMT-1267 following IV administration of XMT-1660 to MX-1 human TNBC xenograftbearing mice at the indicated doses and dose regimens, and as described in FIG.7 and FIG.8. TNBC = triple negative breast cancer; IV = intravenous; SD = standard deviation.

[0061] FIG. 9 is a series of graphs depicting tumor volumes (individual animal) following IV administration of XMT-1660 at the indicated doses and dose regimens in Study 2. Animals (n=4 / group / timepoint) were euthanized on days 4, 8, 11,15, 18, 22, and 29 and tumors were harvested for PK analysis. Doses are shown by antibody / payload.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0062] FIG. 10 is a graph depicting mean plasma concentration of conjugated payload (XMT-1267) following IV dosing of XMT-1660 to mice bearing human MX-1 xenografts at the indicated doses and dose regimens in Study 2.

[0063] FIG. 11 is a graph depicting the model-estimated drug effect on decreasing cycling cell growth as a function of conjugated drug (XMT-1267) in plasma.

[0064] FIG. 12 is a graph depicting the model-estimated tumor growth inhibition as a function of time above the threshold conjugated drug (XMT-1267) concentration of 456 ng / mL.

[0065] FIG. 13 is a graph depicting quantitation of PD-L1 protein (Fig. 13A) and CD8 protein (Fig 13B) as measured by immunohistochemistry frommBR9013 tumors 10 days after treatment with vehicle, non-bmding control ADC or XMT-1660.

[0066] FIG. 14 is a bar graph showing anti-HER2 and anti-B7-H4 antibody binding capacity of SKBR3 topoisomerase I inhibitor-resistant cell line compared to parental cells. Both parental and resistant SKBR3 cells were stained with 125 nM trastuzumab (left bars), anti-B7-H4 (middle bars), or a non-bmding control antibody (right bars), counterstained with a secondary AF-647 goat anti-human antibody and the geometric mean was measured using flow cytometry. N=2 biological replicate wells.

[0067] FIG. 15 is a bar graph bar graph showing antibody binding capacity of the anti-B7-H4 antibody to CAMA-1 topoisomerase I inhibitor-resistant cell line compared to parental cells. Both parental and resistant CAMA-1 cells were stained with 125 nM anti-B7-H4 or non-binding control antibody, counterstained with a secondary AF-647 goat anti-human antibody and the geometric mean was measured using flow cytometry. N=2 biological replicate wells.

[0068] FIG. 16 is a series of graphs depicting dose response curves of SKBR3 topoisomerase I inhibitor-resistant cell line compared to parental cells. Both parental and resistant SKBR3 cells were treated with SN-38, Exatecan, Trastuzumab-Dxd (Enhertu), B7-H4-vcMMAE, XMT-1660, Trastuzumab-AF-HPA or non-binding-AF-HPA control ADC for 4 days and the cell viability was measured via CTG assay. N=2 biological replicate wells.

[0069] FIG. 17 is a series of graphs depicting dose response curves of CAMA-1 topoisomerase I inhibitor-resistant cell line compared to parental cells. Both parental and resistant CAMA-1 cells were treated with SN-38, B7-H4-vcMMAE, XMT-1660, or non-binding-AF-HPA control ADC for 6 days and the cell viability was measured via CTG assay. N=3 biological replicate wells.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0070] FIG. 18 is a plot showing treatment-related adverse events observed in greater than or equal to 10% of patients. Left column = aggregated across all doses; Center column = patients treated with 38.1 mg / m2- 67.4 mg / m2XMT-1660 per cycle; Right column = patients treated with > 76,2 mg / m2XMT-1660 per cycle.

[0071] FIG. 19 is a waterfall plot of best change in target lesion size from baseline for all evaluable participants treated with XMT-1660 by B7-H4 expression categorized as either above or below a TPS of 70%, and segregated by dose intensity. * indicates ongoing treatment; C:::confirmed responder; U:::ongoing unconfirmed responder.

[0072] FIG. 20 is a waterfall plot of best change in target lesion size from baseline for evaluable participants with B7-H4 TPS > 70% treated with > 76.2 mg / m2XMT-1660 per cycle by tumor type. * indicates treatment ongoing as of data cut-off date. PR:::confirmed partial response. CR:::confirmed complete response. uPR::::unconfirmed partial response as of data cut-off date. Confirmatory scans following the data cut-off date indicated that the two subjects with uPR progressed, however, both these patients had protocol-mandated dose delays for proteinuria prior to the confirmatory scans.

[0073] FIG. 21 is a waterfall plot of best change in target lesion size from baseline for evaluable participants with B7-H4 IPS > 70% treated with 38.1 mg / m2- 67.4 mg / m2XMT-1660 per cycle by tumor type. * indicates treatment ongoing as of data cut-off date. PR = confirmed partial response.

[0074] FIG. 22 is a spider plot showing duration (weeks) and extent (change in size of target lesion vs. baseline) of response in evaluable patients with B7-H4 TPS greater than or equal to 70% treated with XMT-1660 from 38.1 mg / m2to 67.4 mg / m2per cycle. Arrows indicate treatment ongoing at the time of the data cut-off. Dotted vertical line at -7 weeks indicates median progression-free survival shown by standard of care single-agent chemotherapy in late-stage TNBC in the ASCENT Phase 3 clinical trial (Bardia et al. NEJM 2021 April 22; 384(16): 1529-1541).

[0075] FIG. 23 is a waterfall plat of best change in target lesion size from baseline in evaluable triple-negative breast cancer patients that with B7-H4 TPS greater than or equal to 70%, who received XMT-1660 at a dose intensity of 38.1 mg / m2to 67.4 mg / m2per cycle and who had received a prior topoisomerase 1 inhibitor ADC therapy. * indicates treatment ongoing as of data cut-off date. PR = confirmed partial response. T indicates previously treated with one topoisomeraseAttorney Docket No.43704-02721 MRSN-047 / 001WO 1 inhibitor antibody-drug conjugate. TT indicates previously treated with more than one topoisomerase 1 inhibitor antibody-drug conjugate.

[0076] FIG. 24 is a plot of all treatment related adverse events (TRAEs) reported in 10% or more of TNBC patients treated with a dose intensity between 38.1 mg / m2and 67.4 mg / m2during the dose escalation / backfill portion of the phase 1 trial of XMT-1660 (n=44).

[0077] FIG. 25 is a plot of the preliminary Progression Free Survival (PFS) for the B7-H4-High (TPS>70%) TNBC patients treated with between 38.1 mg / m2to 67.4 mg / m2during the dose escalation / backfill portion of the phase 1 trial of XMT-1660 (n=44). One curve shows PFS for patients who had received more than 4 prior lines of therapy and the second curve shows PFS for patients who had received 4 or fewer prior lines of therapy.

[0078] FIG. 26 is a plot of the preliminary Overall Survival (OS) for the B7-H4-High (TPS>70%) TNBC patients treated with between 38.1 mg / m2to 67.4 mg / m2during the dose escalation / backfill portion of the phase 1 trial of XMT-1660 (n::::44). One curve shows OS for patients who had received more than 4 prior lines of therapy and the second curve shows OS for patients who had received 4 or fewer prior lines of therapy.

[0079] FIG. 27 is a waterfall plot showing the tumor reduction of all evaluable patients unselected for B7-H4 expression with ACC-1 treated with any dose of XMT-1660. * indicates treatment ongoing as of data cut-off date. PR = confirmed partial response. CR = confirmed complete response. uPR = unconfirmed partial response as of data cut-off date.DETAILED DESCRIPTION

[0080] The disclosure provides methods of treating a subject having a cancer or solid tumor, comprising administering to the subject a B7-H4-targeted antibody-drug conjugate (XMT-1660) that specifically binds to the extracellular region of B7-H4. The disclosure provides methods of treating a subject having adenoid cystic carcinoma (ACC), TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, or solid tumors thereof, comprising administering to the subject a B7-H4-targeted antibody-drug conjugate (XMT-1660) that specifically binds to the extracellular region of B7-H4. Specifically, the invention provides dosing regimens for the treatment of B7-H4 expressing cancers or solid tumors by administration as an intravenous infusion. XMT-1660 is a B7-H4-targeted antibody-drug conjugateAttorney Docket No. 43704-02721 MRSN-047 / 001WO comprising a B7-H4 modified antibody and two molecules of a fully synthetic macromolecular linker-payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA). The fully synthetic macromolecular linker-payload is conjugated to the modified B7-H4-antibody in a site-specific manner enabled by glycan remodeling of the antibody at an asparagine group of the antibody. In some aspects, the asparagine is in the conserved Fc region of the antibody. In some aspects, the asparagine group is N297 according to EU numbering. The average drug-to-antibody ratio (DAR) of the B7-H4-targeted antibody-drug conjugate is approximately 6.

[0081] More specifically, Example 6 of the present disclosure describes an ongoing clinical study of the use of XMT-1660 in patients with refractory solid tumors. As described further in Example 6, XMT-1660 treatment with XMT-1660 was generally well -tolerated. There were no treatment-related grade 4 or 5 events. Of the 130 participants treated to-date with XMT-1660, 2.3% (n::::3 / 130) of the participants had treatment discontinued due to a treatment-related adverse event (“AE”), dose delays due to a treatment-related AE occurred in 12.3% (n=16 / 130) of participants, and 9.2% (n=12 / 130) required dose reductions due to a treatment-related AE. At the highest dose levels studied to-date, there have been no observed signs or symptoms of high-grade ocular toxicity, neutropenia, peripheral neuropathy, or thrombotic microangiopathy seen with other targets or ADC platforms. Interstitial lung disease or pneumonitis and bleeding events have also not been dose limiting for XMT-1660. The most frequent grade 3 AEs were aspartate aminotransferase / aspartate transaminase (“AST”) increases and proteinuria. There was a trend toward increased frequency of these two events at higher doses, and proteinuria became an important cause of dose delays at higher doses.

[0082] Accordingly, the results presented in Example 6 demonstrate that there exists a need for effective compositions and methods of treatment of cancers involving a B7-H4 antibody-drug conjugate (e.g. XMT-1660) that provide for the management of proteinuria and thus allow administration of the B7-H4 antibody-drug conjugate at higher dose intensities while mitigating the risk of proteinuria, in order to balance the potential for meaningful clinical activity with clinical safety. The present disclosure provides such methods of treatment that combine B7-H4 antibody-drug conjugates (e.g, XMT-1660) at higher doses and agents for the management of proteinuria, as described in further detail herein.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0083] In some aspects, patients with cancer, e.g., ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer are intravenously administered XMT-1660 once every 3 weeks (i.e. 21 day cycle) or once every 4 weeks (i.e. 28 day cycle). Accordingly, the invention features methods of treating cancer, e.g., ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer by administering to a subject, i.e., human, in a dose escalation study an infusion dose of XMT-1660 at about 7.2 mg / m2, about 14.4 mg / m2, about 21.6 mg / m2, about 25.15 mg / m2, about 28.7 mg / m2, about 33.4 mg / m2, about 38.1 mg / m2, about 44.5 mg / m2, about 50.7 mg / m2, about 59.0 mg / m2, about 67.4 mg / m2, about 77.5 mg / m2, about 80.0 mg / m2, about 87.6 mg / m2, about 95.0 mg / m2, or about 115.0 mg / m2once every 3 weeks (i.e. 21 day cycle) or every 4 weeks (i.e. 28 day cycle).

[0084] In some aspects, patients with cancer, e.g., ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer are intravenously administered XMT-1660 on day 1 and on day 8 of a 4 week cycle. Accordingly, the invention features methods of treating cancer, e.g., ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer by administering to a subject, i.e., human, an infusion dose of XMT-1660 at about 7.2 mg / m2, about 14.4 mg / m2, about 21.6 mg / m2, about 25.15 mg / m2, about 28.7 mg / m2, about 33.4 mg / m2, about 38.1 mg / m2, about 44.5 mg / m2, about 50.7 mg / m2, about 59.0 mg / m2, about 67.4 mg / m2, about 77.5 mg / m2, about 80.0 mg / m2, about 87.6 mg / m2, about 95.0 mg / m2, or about 115.0 mg / m2on day 1 and on day 8 of a 4 week cycle (i.e. 28 day cycle).

[0085] In some embodiments, the subject has a B7-H4 expressing cancer. In some aspects, the subject has a B7-H4 expressing tumor.

[0086] In some embodiments the subject has been identified as having B7-H4 expression. In some embodiments, the B7-H4 expression is in the form of a B7-H4 expressing tumor. B7-H4 expression is detected by methods known in the art. For example, by immunohistochemistry (IHC) analysis, fluorescent in situ hybridization (FISH) assay or RNA expression analysis of B7-H4 transcript or other genes related to cancer measured in tumor samples. In some embodiments the subject has been identified as a B7-H4 expressing tumor by determination of a tumor proportion score (TPS), for example, as described herein. In some embodiments the subject has been identified as having a B7-H4 expressing tumor by determination of a B7-H4+ tumor proportion score ofAttorney Docket No. 43704-02721 MRSN-047 / 001WO greater than or equal to 50%, as described herein. Blood-based biomarkers, which may include serum cytokines, circulating immune cells, and circulating tumor cells can also be used to determine the B7-H4 expression levels.B7-H4 Antibodies

[0087] Provided by the disclosure are isolated antibodies that bind to B7-H4, a Type I transmembrane protein found, for example, on the surface of antigen presenting cells (APC). The B7-H4 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibodies comprising the heavy chain and / or light chain CDRs discussed herein.

[0088] In some embodiments, B7-H4 antibodies of the disclosure specifically bind to an epitope on the full-length human B7-H4 protein comprising the amino acid sequence:MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCTFEPDIKLSDIVI QWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNASLRLKNVQLTDAGTY KCYIITSKGKGNANLEYKTGAFS EVNVDYNASSETLRCEAPRWFPQPTVVWASQVDQG ANFSEVSNTSFELNSENVITMKVVSVLYNVITNNTYSCMIENDIAKATGDIKVTESEIKRRSH LQLLNSKASLCVSSFFAISWALLPLSPYLMLK (SEQ ID NO: 1).

[0089] In some embodiments, a B7-H4 antibody is a human antibody. In some embodiments, the B7-H4 antibody modulates B7-H4 activity. In some embodiments, the antibody is one that induces an Antibody-dependent cellular cytotoxicity (ADCC) response in a subject that receives the antibody. In some embodiments, the B7-H4 antibody does not inhibit T-Cell suppression activity of B7-H4. The B7-H4 antibody of this disclosure can be, for example, a full- length antibody. Alternatively, B7-H4 antibodies can be antibody fragments, such as Fab, Fab' or Fab' 2 fragments or single chain antibodies (e.g., scFv). In some embodiments, the antibody is an IgGl antibody.

[0090] In some embodiments, a B7-H4 antibody comprises a heavy chain variable region and a light chain variable region. In some embodiments, a B7-H4 antibody comprises at least one heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, a B7-H4 antibody comprises two heavy chains, wherein each heavy chain comprises a heavy chain variable region and at least aAttorney Docket No.43704-02721 MRSN-047 / 001WO portion of a heavy chain constant region, and two light chains, wherein each light chain comprises a light chain variable region and at least a portion of a light chain constant region,

[0091] In some embodiments, a human B7-H4 antibody comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG (for example, an IgGl, IgG2, IgG3, or IgG4, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from kappa (K) and lambda (X). In some embodiments, a human antibody described herein comprises a human IgG constant region. In some embodiments, a human antibody described herein comprises a human IgG4 heavy chain constant region. In some embodiments, a human antibody described herein comprises a human IgG4 constant region and a human K light chain.

[0092] In some embodiments, when effector function is desirable, a human B7-H4 antibody comprising a human IgGl heavy chain constant region or a human IgG3 heavy chain constant region is selected. In some embodiments, when effector function is not desirable, a human B7-H4 antibody comprising a human IgG4 or IgG2 heavy chain constant region is selected.

[0093] In some embodiments, the antibody of this disclosure is characterized by its particular functional features or properties of the antibody. For example, the antibody binds specifically to human B7-H4. Typically, the antibody of this disclosure binds to B7-H4 with high affinity, for example with a KD of 1 X 10'7M or less. The anti-B7-H4 antibody of this disclosure typically exhibits one or more of the following characteristics:(a) binds to human B7-H4 with a KD of 1 X IO'7M or less; and / or(b) binds to human CHO cells transfected with B7-H4 (e.g. human B7-H4).

[0094] In some embodiments, the antibody binds to human B7-H4 with a KD of 5 X 10'8M or less, bind to human B7-H4 with a KD of 2 X 10'8M or less, binds to human B7-H4 with a KD of 5 x 10'9M or less, binds to human B7-H4 with a KD of 4 X 10"9M or less, binds to human B7-H4 with a KD of 3 x 10'9M or less, binds to human B7-H4 with a KD of 2 X 10'9M or less or binds to human B7-H4 with a KD of 1 X 10'9M or less.

[0095] Standard assays to evaluate the binding ability of the antibody toward B7-H4 are known in the art, including for example, ELISAs, Western blots, RIAs and flow cytometry analysis. The binding kinetics (e.g., binding affinity) of the antibody also can be assessed by standard assays known in the art, such as by ELISA, Scatchard and Biacore® system analysis.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0096] Potential therapeutic mAbs must not only bind to their target but must also be free from “developability issues” such as poor stability or high levels of aggregation. We describe guideline values for five metrics thought to be implicated in poor developability: the total length of the complementarity-determining regions (CDRs), the extent and magnitude of surface hydrophobicity, positive charge and negative charge in the CDRs, and asymmetry in the net heavy- and light-chain surface charges. The guideline cutoffs for each property were derived from the values seen in CSTs, and a flagging system is proposed to identify nonconforming candidates.

[0097] The nucleic acid and amino acid sequence of the monoclonal B7-H4 antibody of the disclosure is provided below. The complementarity determining regions (CDRs) of the heavy chain and the light chain are underlined in the amino acid sequences presented below. The amino acids encompassing the complementarity determining regions (CDR) as shown below are defined in accordance to the IMGT numbering system (See IMGT*\ the international ImMunoGeneTics information system13*. Available online: http: / / www.imgt.org / ).

[0098] In some embodiments, the B7-H4 antibody of the disclosure comprises CDR sequences as set forth below.Region Sequence Fragment by IMGT Residue range based on IMGT numbering CDR-H1 GFIVSRNY (SEQ ID NO: 2) 26-33CDR-H2 IYGSGRT (SEQ ID NO: 3) 51-57CDR-H3 ARDADYGLDV (SEQ ID NO: 4) 96-105CDR-L1 QSVSSSY (SEQ ID NO: 5) 27-33CDR-L2 GAS (SEQ ID NO: 6) 51-53CDR-L3 QQYGSSPLYT (SEQ ID NO: 7) 90-99Region Sequence Fragment by Kabat Residue range based on Kabat numbering CDR-H1 RNYMN (SEQ ID NO: 15) 31-35CDR-H2 VIYGSGRTDSADSVKG (SEQ ID NO: 16) 50-65CDR-H3 DADYGLDV (SEQ ID NO: 17) 98-105CDR-L1 RASQSVSSSYLA (SEQ ID NO: 18) 24-35CDR-L2 GASSRAT (SEQ ID NO: 19) 51-57CDR-L3 QQYGSSPLYT (SEQ ID NO: 7) 90-99

[0099] In some embodiments, the B7-H4 antibody of the disclosure comprises a light chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 8. In some embodiments, the B7-H4 antibody of the disclosure comprises a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 9. In embodiments, the B7-H4 antibody of the disclosure comprises a light chain variable region comprising or consisting of theAttorney Docket No. 43704-02721 MRSN-047 / 001WO amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region comprising or consisting of the amino acid sequence of SEQ ID NO: 9.

[0100] The VL chain of B7-H4 VL (SEQ ID NO:8) comprises or consists of the amino acid sequence:EIA TOSPGTLSLSPGERATLSCRASOSVSSSYIAWYOQKPGOAPRLLIYGASSRATG IPDRFSGSGSGTDFTLTISRLEPEDFAVYYCOOYGSSPI. YTFGOGTKLEIK (SEQ ID NO: 8)

[0101] The VH chain of B7-H4 (SEQ ID NO: 9) (also referred to herein as the XMT-1604 VH) comprises or consists of the ammo acid sequence:EVQLVESGGGLIOPGGSLRLSCAASGFIVSRNYMNWVRQAPGKGLEWVSVIYGSGRTDSA DSVKGRFTISRDNSKNTLYLOMNSLRAEDTAVYYCARDADYGLDVWGOGTTVTVSS(SEQ ID NO: 9).

[0102] The B7-H4 variable heavy chain is also referred to herein as the XMT-1604 variable heavy chain.

[0103] In some embodiments the B7-H4 antibody (XMT-1604) comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence I YGSGRT (SEQ ID NO: 3), and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4)

[0104] In some embodiments the B7-H4 antibody (XMT-1604) comprises a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7).

[0105] In some embodiments, the B7-H4 antibody of the disclosure has a light chain constant region comprising or consisting of the amino acid sequence:RTVAAPSVTIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTL, TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0106] The B7-H4 light chain constant region (SEQ ID NO: 10) is also referred to herein as B7-H4 LCAttorney Docket No. 43704-02721 MRSN-047 / 001WO

[0107] In some embodiments, the antibody of the d isclosure comprises a light chain comprising or consisting of a light chain variable region amino acid sequence and a light chain constant region ammo acid sequence. In embodiments, the antibody of the disclosure comprises a light chain (variable and constant regions) of the disclosure, for example, comprises or consists of the amino acid sequence of SEQ ID NO: 12.

[0108] In embodiments, the B7-H4 antibody of the disclosure has a IgGl heavy chain constant region comprising or consisting of the amino acid sequence:ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVWSWNSGALTSGVHTFPAVLQSSGL YS LS S WTVPS S SLGTQTYICN VNI IKPSNTK VDKKVEPKSCDKT1 ITC PPCP APELLGGPS VF LFPPKPKDTLMISRTPEVTCWVDVSIIEDPEVKFNWYVDGVEVIINAKTKPREEQYNSTYR WSVLTVLFIQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 11). The B7-H4 IgGl heavy chain constant region (SEQ ID NO: 11) is also referred to herein as B7-H4 HC. In some embodiments, the IgGl heavy chain constant region comprising or consisting of SEQ ID NO: 11 further comprises one or more amino acids at the N-terminus or C -terminus. In some embodiments, the IgGl heavy chain constant region comprises a C -terminal lysine.

[0109] In some embodiments, the antibody of the disclosure comprises a heavy chain set forth in SEQ ID NO: 14. In some embodiments, the antibody of the disclosure comprises a heavy chain set forth in SEQ ID NO: 13. In some embodiments, the antibody of the disclosure comprises a heavy chain set forth in SEQ ID NO: 13 without the C -terminal lysine. In some embodiments, the antibody of the disclosure comprises or consists of a heavy chain variable region amino acid sequence (e.g., SEQ ID NO: 9) and a heavy chain constant region amino acid sequence (e.g., SEQ ID NO: 11).

[0110] In yet another embodiment, the B7-H4 antibody of this disclosure comprises a heavy and light chain variable region comprising amino acid sequences that are homologous to the amino acid sequences of the antibody described herein and wherein the antibody retains the desired functional properties of the anti-B7-H4 antibody of this disclosure. For example, this disclosure provides an isolated monoclonal antibody or antigen binding portion thereof, comprising a heavy¬ chain variable region and a light chain variable region, wherein:Attorney Docket No. 43704-02721 MRSN-047 / 001WO (a) the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to an ammo acid sequence of SEQ ID NO: 9;(b) the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an ammo acid sequence of SEQ ID NO: 8;(c) the antibody binds to human B7-H4 with a KD of 1 x 10⁻⁷ M or less; and(d) the antibody binds to human CHO cells transfected with B7-H4.

[0111] In various embodiments, the antibody can be, for example, a human antibody, a humanized antibody or a chimeric antibody.

[0112] In other embodiments, the VH and / or VL amino acid sequences may be 85%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above. A B7-H4 antibody having VH and VL regions having high (i.e. 80% or greater) homology to the VH and VL regions of the sequences set forth above, can be obtained by mutagenesis (e.g., site-directed or PCR- mediated mutagenesis) of nucleic acid molecules encoding the amino acid sequences set forth in SEQ ID NO: 9, followed by testing of the encoded altered antibody for retained function (i.e., the functions set forth in (c) and (d) above), using the functional assays described herein.

[0113] In a preferred embodiment, the heavy chain variable region CDR2 sequence comprises an amino acid sequence set forth in SEQ ID NO: 3, and conservative modifications thereof; and the light chain variable region CDR2 sequence comprises an amino acid sequence set forth in SEQ ID NO: 6 and conservative modifications thereof. In another preferred embodiment, the heavy chain variable region CDR1 sequence comprises an amino acid sequence set forth in SEQ ID NO: 2 and conservative modifications thereof; and the light chain variable region CDR1 sequence comprises an amino acid sequence set forth in SEQ ID NO: 5 and conservative modifications thereof. In another preferred embodiment, the heavy chain variable region CDR3 sequence comprises an amino acid sequence set forth in SEQ ID NO: 4 and conservative modifications thereof; and the light chain variable region CDR3 sequence comprises an amino acid sequence set forth in SEQ ID NO: 7 and conservative modifications thereof.

[0114] In various embodiments, the antibody can be, for example, a human antibody, humanized antibody or chimeric antibody,

[0115] In some embodiment, the antibody binds to the same epitope on human B7-H4 as any of the B7-H4 monoclonal antibodies of this disclosure (i.e., antibodies that have the ability to cross-compete for binding to B7-H4 with any of the monoclonal antibodies of this disclosure).Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0116] Accordingly, another embodiment of this disclosure pertains to an isolated monoclonal antibody or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising an amino acid sequence SEQ ID NO: 9 respectively and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising an amino acid sequence of SEQ ID NOs: 5, 6 and 7 respectively.

[0117] Accordingly, in another embodiment, this disclosure provides isolated anti-B7-H4 monoclonal antibody or antigen binding portions thereof, comprising a heavy chain variable region comprising: (a) a VH CDR1 region comprising an amino acid sequence comprising SEQ ID NO: 2; or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 2; (b) a VH CDR2 region comprising an amino acid sequence comprising SEQ ID NO: 3; or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 3; (c) a VH CDR3 region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NO: 4.

[0118] In some embodiments, the antibody disclosed herein comprises a heavy chain having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 14 and a light chain having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 12.

[0119] In some embodiments, the antibody disclosed herein comprises a heavy chain having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 13 and a light chain having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 12.

[0120] In some embodiments, the antibody disclosed herein comprises a combination of heavy chain and light chain amino acid sequences comprising a heavy chain 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: 13 and a light chain 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: 12,

[0121] In some embodiments, the antibody disclosed herein comprises a combination of heavy chain and light chain amino acid sequences comprising a heavy chain amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acidAttorney Docket No. 43704-02721 MRSN-047 / 001WO sequence of SEQ ID NO: 14 and a light chain amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the ammo acid sequence of SEQ ID NO: 12.

[0122] In some embodiments, the antibody disclosed herein comprises a heavy chain 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: 13 and a light chain 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: 12.

[0123] In some embodiments, the antibody disclosed herein comprises a heavy chain 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 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: 12.

[0124] In some embodiments, the antibody disclosed herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 14 and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 13 and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 13 and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 13 without the C-terminal lysine, and a light chain comprising an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain consisting of an amino acid sequence of SEQ ID NO: 14 and a light chain consisting of an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain consisting of an amino acid sequence of SEQ ID NO: 13 and a light chain consisting of an amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody disclosed herein comprises a heavy chain consisting of an amino acid sequence of SEQ ID NO: 13 without the C-terminal lysine, and a light chain consisting of an amino acid sequence of SEQ ID NO: 12,

[0125] In some embodiments, the antibody disclosed herein comprises a combination of heavy chain and light chain amino acid sequences of the heavy chain amino acid sequence of SEQ ID NO: 14 and the light chain amino acid sequence of SEQ ID NO: 12.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0126] In some embodiments, the antibody disclosed herein comprises a combination of heavy chain and light chain amino acid sequences of the heavy chain amino acid sequence of SEQ ID NO: 13 and the light chain amino acid sequence of SEQ ID NO: 12.

[0127] In some embodiments, the antibody disclosed herein comprises a combination of heavy chain and light chain amino acid sequences of the heavy chain amino acid sequence of SEQ ID NO: 13 without the C -terminal lysine, and the light chain amino acid sequence of SEQ ID NO: 12.

[0128] In some embodiments, the antibody disclosed herein comprises the heavy chain amino acid sequence of SEQ ID NO: 14 and the light chain amino acid sequence of SEQ ID NO: 12.

[0129] In some embodiments, the antibody disclosed herein comprises the heavy chain amino acid sequence of SEQ ID NO: 13 and the light chain amino acid sequence of SEQ ID NO: 12.

[0130] In some embodiments, the antibody disclosed herein comprise the heavy chain amino acid sequence of SEQ ID NO: 13 without the C-terminal lysine, and the light chain amino acid sequence of SEQ ID NO: 12.

[0131] The antibody disclosed herein comprises a heavy chain variable region having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 9 and a light chain variable region having an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence consisting of SEQ ID NOs: 8.

[0132] In some embodiments, the three heavy chain CDRs of the antibody disclosed herein include a heavy chain complementarity determining region 1 (CDRH1) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 2; a heavy chain complementarity determining region 2 (CDRH2) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 3; and a heavy chain complementarity determining region 3 (CDRH3) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 4; and a heavy chain amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence SEQ ID NO: 14.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0133] In some embodiments, the three heavy chain CDRs of the antibody disclosed herein include a heavy chain complementarity determining region 1 (CDRH1) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 2; a heavy chain complementarity determining region 2 (CDRH2) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 3; and a heavy chain complementarity determining region 3 (CDRII3) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to SEQ ID NO: 4; and a heavy chain amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence SEQ ID NO: 13.

[0134] The three light chain CDRs of the antibody disclosed herein include a light chain complementarity determining region 1 (CDRL1) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO. 5; a light chain complementarity determining region 2 (CDRL2) that includes an ammo acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 6; and a light chain complementarity determining region 3 (CDRL3) that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 7.

[0135] The antibody include a combination of heavy chain CDR and light chain CDR sequences that include a CDRH1 that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 2; a CDRH2 that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence comprising SEQ ID NO: 3; a CDRH3 that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% to a sequence comprising SEQ ID NO: 4; a CDRL1 that includes an ammo acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence selected from the group consisting of SEQ ID NO: 5; a CDRL2 that includes an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a sequence of SEQ ID NO: 6; and a CDRL3 that includes an ammo acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to a of SEQ ID NO: 7; and a heavy chain amino acidAttorney Docket No.43704-02721 MRSN-047 / 001WO 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: 45.

[0136] The three heavy chain CDRs of the antibody disclosed herein include a CDRHl that includes an amino acid sequence selected from the group comprising SEQ ID NO: 2 a CDRH2 that includes an amino acid sequence comprising SEQ ID NO: 3; and a CDRH3 that includes an ammo acid sequence comprising SEQ ID NO: 4; and a heavy chain amino acid sequence comprising SEQ ID NO: 14.

[0137] The three heavy chain CDRs of the antibody disclosed herein include a CDRHl that includes an amino acid sequence selected from the group comprising SEQ ID NO: 2 a CDRH2 that includes an amino acid sequence comprising SEQ ID NO: 3; and a CDRII3 that includes an amino acid sequence comprising SEQ ID NO: 4; and a heavy chain ammo acid sequence comprising SEQ ID NO: 13.

[0138] The three light chain CDRs of the antibody disclosed herein include a CDRL1 that has an amino acid sequence of SEQ ID NO: 5; a CDRL2 that has an ammo acid sequence of SEQ ID NO: 6; and a CDRL3 that has an amino acid sequence of SEQ ID NO: 7. The antibody disclosed herein include a combination of heavy chain CDR and light chain CDR sequences that include a CDHR1 that includes an ammo acid sequence selected comprising SEQ ID NO: 2; a CDRH2 that includes an ammo acid sequence comprising SEQ ID NO: 3; a CDRH3 that includes an amino acid sequence comprising SEQ ID NO: 4; a CDRL1 that has an amino acid sequence of SEQ ID NO: 5; a CDRL2 that has an amino acid sequence of SEQ ID NO: 6; and a CDRL3 that has an amino acid sequence of SEQ ID NO: 7; and a heavy chain amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14. The antibody disclosed herein comprises a combination of heavy chain complementarity determining region and light chain complementarity determining region amino acid sequences selected from the group consisting of (i) the CDRHl amino acid sequence of SEQ ID NO: 2, the CDRH2 amino acid sequence of SEQ ID NO: 3, the CDRH3 amino acid sequence of SEQ ID NO: 4, the CDRL1 amino acid sequence of SEQ ID NO: 5, the CDRL2 amino acid sequence of SEQ ID NO: 6, the CDRL3 amino acid sequence of SEQ ID NO: 7, and a heavy chain amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

[0139] In some embodiments, the antibody disclosed herein comprises a CDRHl amino acid sequence of SEQ ID NO: 2, a CDRH2 ammo acid sequence of SEQ ID NO: 3, a CDRH3 amino acid sequence of SEQ ID NO: 4, a CDRL1 amino acid sequence of SEQ ID NO: 5, a CDRL2Attorney Docket No.43704-02721 MRSN-047 / 001WO amino acid sequence of SEQ ID NO: 6, a CDRL3 amino acid sequence of SEQ ID NO: 7, and a heavy chain amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

[0140] In some embodiments the B7-H4 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7); wherein the antibody further comprises a light chain variable region that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the ammo acid sequence of SEQ ID NO: 8 and comprises a heavy chain variable region that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9.

[0141] In some embodiments the B7-H4 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity’ determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7); wherein the antibody further comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the ammo acid sequence of SEQ ID NO: 12 and comprises a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 13,Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0142] In some embodiments the B7-H4 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7); wherein the antibody further comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 12 and comprises a heavy chain that is 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.

[0143] In some embodiments the B7-H4 antibody comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), and a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7); wherein the antibody further comprises a light chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 12 and comprises a heavy chain that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, 99% or more identical to the amino acid sequence of SEQ ID NO: 13 and does not comprise the C -terminal lysine of SEQ ID NO: 13, Modified B 7-H 4 Antibodies

[0144] In some embodiments, the B7-H4 antibody is a modified B7-H4 antibody. As used herein, the term “modified B7-H4 antibody” can be used to describe a B7-H4 antibody of theAttorney Docket No.43704-02721 MRSN-047 / 001WO disclosure having a modification including a mutation, deletion, or substitution. As used herein, the terms “modified B7-H4 antibody” can be used to describe a B7-H4 antibody having a modification to an amino acid of the antibody including covalent attachment of a chemical moi ety to the ammo acid side. In some embodiments, a “modified B7-H4 antibody” can have a sugar or sugar derivative moiety covalently attached to an amino acid of the antibody. In some embodiments, a “modified B7-H4 antibody” can have a sugar or sugar derivative moiety replaced by a different sugar or sugar derivative moiety.

[0145] In some embodiments of the modified B7-H4 antibody, * denotes a direct or indirect attachment to the rest of the modified B7-H4 antibody. In some embodiments, S” is a sugar or a derivatized sugar. In some embodiments, / X” is a functional group being capable of forming a covalent bond with a functional group of a macromolecular linker-payload (i.e., drug or linker-drug moiety).

[0146] In some embodiments, the modified B7-H4 antibody, prior to conjugation, comprises a sugar-derivative moiety of *— S"— A"

[0147] In some embodiments, the modified B7-H4 antibody comprises an asparagine group in the constant region of the antibody. The constant region of IgG antibodies is well conserved and each amino acid can be identified by EU number. See Edelman, GM. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969). In some aspects, the asparagine group is in the region 290-305 (e.g., at N297; EU numbering). Asparagine 297 is found in the conserved Fc region of the heavy chain of an IgG antibody. In some embodiments, the sugar- derivative moiety is directly or indirectly attached to the asparagine group (e.g., at N297).

[0148] In some embodiments, an asparagine of the B7-H4 antibody heavy chain constant region set forth in SEQ ID NO: 11 is modified. In some embodiments, the asparagine to be modified (N297 according to EU numbering) corresponds to position 180 (N180) of SEQ ID NO: 11. In some aspects, the macromolecular linker-payload (e.g., drug or linker-drug moiety) of the B7-H4 ADC is attached to N180 of SEQ NO: 11.

[0149] In some embodiments, an asparagine of the B7-H4 antibody heavy chain set forth in SEQ ID NO: 14 is modified. In some embodiments, the asparagine to be modified (N297 according to EU numbering) corresponds to position 296 (N296) of SEQ ID NO: 14. In some aspects, the macromolecular linker-payload (e.g., drug or linker-drug moiety) of the B7-H4 ADC is attached to N296 of SEQ ID NO: 14.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0150] In some embodiments, an asparagine of the B7-H4 antibody heavy chain set forth in SEQ ID NO: 13 is modified. In some embodiments, the asparagine to be modified (N297 according to EU numbering) corresponds to position 296 (N296) of SEQ ID NO: 13. In some aspects, the macromolecular linker-payload (e.g., drug or linker-drug moiety) of the B7-H4 ADC is attached to N296 of SEQ ID NO: 13.

[0151] In some embodiments, the modified B7-H4 antibody, prior to conjugation, comprises *— GICNAC — S" — A"a modified-GlcNAc moiety,, wherein GIcNAc is N-acetylglucosamine.

[0152] In some embodiments, the modified-GlcNAc moiety is connected to the rest of the modified B7-II4 antibody via the Cl position of the GIcNAc. In some embodiments, the modified-GlcNAc moiety further comprises a fucose.

[0153] In some embodiments, the modified-GlcNAc moiety is directly or indirectly attached to the asparagine group (e.g., at N297).

[0154] In some embodiments, the modified B7-H4 antibody is conjugated to the drug via a linker moiety (i.e., macromolecular linker-payload or linker-drug moiety) via a covalent bond formed between A” and a functional group of the Linker-Drug moiety.

[0155] In some embodiments, the modified B7-H4 antibody of the present disclosure is obtained by a process comprising:(a) contacting a glycoprotein (e.g., a B7-H4 antibody glycan) comprising a B7-H4 antibody and a core-GlcNAc moiety with an endoglycosidase, thereby forming an intermediate antibody comprising the antibody and a terminal- GIcNAc moiety' and, optionally, the terminal-GlcNAc moiety further comprises a fucose; and(b) contacting the intermediate antibody with a compound having the structure of It Q II A ”, in the presence of a glycosyltransferase, thereby forming the modified B7-H4*— GICNAC — S" — A" antibody comprising the antibody and the modified-GlcNAc moiety,, and, optionally, the modified-GlcNAc moiety is attached to the rest of the modified B7-H4 antibody the Cl position of the GIcNAc; whereinGlcNAc is N-acetylglucosamine;S” is a sugar or a derivatized sugar;A” is azido, keto, or alkynyl; andP” is uridine diphosphate (UDP), guanosine diphosphate (GDP) or cytidine diphosphate (CDP).Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0156] In some embodiments, steps (a) and (b) are conducted sequentially. In some embodiments, steps (a) and (b) are conducted concurrently,

[0157] In some embodiments, the B7-H4 antibody is an IgGl antibody.

[0158] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety.

[0159] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises one or more core-GlcNAc moiety connected to each heavy chain of the antibody.

[0160] In some embodiments, the core-GlcNAc moiety further comprises a fucose.

[0161] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises two or more core-GlcNAc moiety connected to the full-length antibody.

[0162] In some embodiments, the antibody is a full-length antibody, and the antibody glycan comprises two core-GlcNAc moieties connected to the full-length antibody.

[0163] In some embodiments, at least one of the two or more core-GlcN Ac moieties further comprises a fucose.

[0164] In some embodiments, each of the two or more core-GlcNAc moiety further comprises a fucose.

[0165] In some embodiments, the core-GlcNAc moiety is connected to a position of the antibody, wherein the core-GlcNAc moiety does not substantially hinder the antigen-binding site of the antibody.

[0166] In some embodiments, the core-GlcNAc moiety is connected to the Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the CH domain. In some embodiments, the core-GlcNAc moiety is connected to the Fab or Fc fragment of the antibody. In some embodiments, the core-GlcNAc moiety is connected to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody. In some embodiments, the core-GlcNAc moiety is connected to a native N-glycosylation site of the antibody.

[0167] In some embodiments, the antibody is an IgG, antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG.

[0168] In some embodiments, the antibody is an IgG antibody and the core-GlcNAc moiety is connected to a native N-glycosylation site of the IgG (e.g., the N297 N-glycosylation site of IgG,Attorney Docket No. 43704-02721 MRSN-047 / 001WO EU numbering). In some embodiments, the N297 N-glycosylation site is present in the conserved Fc region of the heavy chain of an IgG antibody at asparagine in the region 290-305 (e.g., at N297).In some embodiments, the intermediate antibody is of Formula (XXII):(FUC)U3Ab— -GlcNAcu4(XXII); wherein:Ab is a B7-H4 antibody; GlcNAc is N-acetylglucosamine; Fuc is fucose; us is 0 or 1; and U is an integer ranging from is 1 to 16.

[0169] In some embodiments, U4 is an integer ranging from 1 to 10. In some embodiments, in is an integer ranging from 1 to 4. In some embodiments, U4 is 1, 2, 3, 4, 5, 6, 7 or 8. In some embodiments, U is I, 2, 3, 4, 5 or 6. In some embodiments, U4 is 1, 2, 3 or 4. In some embodiments, U4 is 2 or 4. In some embodiments, U4 is 1 or 2. In some embodiments, U4 is 1. In some embodiments, U is 2.|00170] In some embodiments, the antibody comprises one core-GlcNAc moiety (e.g., U4 is 1). In some embodiments, the antibody comprises two core-GlcNAc moieties (e.g., U4 is 2).

[0171] In some embodiments, the modified B7-H4 antibody is obtained by the process outlined in Scheme 1. As shown below, contacting an intermediate antibody of Formula (XXIII) comprising one terminal-GlcNAc moiety7with a compound having the structure of P"— S"— A", in the presence of a glycosyltransferase, provides a modified B7-H4 antibody comprising one modified- GlcNAc moiety (e.g., the modified B7-H4 antibody of Formula (XXIIIa)).

[0172] In some embodiments, the modified B7-H4 antibody is obtained by contacting an intermediate antibody of Formula (XXIV) comprising two terminal-GlcNAc moieties with a compound having the structure of P" S" A", inthe presence of a glycosyltransferase, provides a modified B7-H4 antibody comprising two modified-GlcNAc moieties (e.g., the modified B7-H4 antibody of Formula (XXIVa)).Scheme 1(Fucfe (FUC)U3| B-S—A'' |Ab— GlcNAc Glycosyl Transferase Ab— GlcNAc s”(A")(XXIII) (XXIIIa)Attorney Docket No.43704-02721 MRSN-047 / 001WO (F«C)U3(FUC)U3(FUC)U3(FUC)U3I I p.. -S„ -AH GlcNAc - Ab“““ GlcNAc ► A1'— S’’— GlcNAc - Ab - GlcNAc — S"— A" Glycosyl Transferase(XXIVa) wherein U3, Ab, S”, A”, and P” are as defined herein.

[0173] In some embodiments, the antibody glycan to be modified in the process according to the present disclosure comprises a glycan, said glycan comprising a core-GlcNAc moiety, i.e., a GlcNAc moiety that is present at the non-reducing end of the glycan. In some embodiments, the glycan comprises one or more saccharide moieties and may be linear or branched.

[0174] In some embodiments, upon reacting with endoglycosidase, the intermediate antibody may be formed, which comprises a terminal GlcNAc moiety (e.g., the intermediate antibody of Formula (XXIII) or (XXIV)).

[0175] In some embodiments, step (a) of the process (the deglycosylation or trimming) is wherein a mixture of antibody glycoforms G2F, GIF, G0F, G2, Gl, GO, and M5 is converted into intermediate antibodies comprising a terminal GlcNAc moiety which optionally comprises a fucose (e.g., U3 is 0 or 1).

[0176] In some embodiments the endoglycosidase is Endo S or Endo SH, or a combination thereof. In some embodiments the endoglycosidase is Endo SH.

[0177] In some embodiments, step (b) of the process (the formation of the modified B7-H4 antibody) wherein the intermediate antibody comprises a monoclonal antibody (mAb) and a terminal GlcNAc moiety (which optionally comprises a fucose (e.g., U3 is 0 or 1)) on each heavy¬ chain of the monoclonal antibody (mAb).

[0178] In some embodiments, the compound of P " S" A"1SGalN / Xz-UDP (e.g., 4- AzGalNAc-UDP). In some embodiments, the terminal-GlcNAc moiety is *-GlcNAc-GalNAz or *-GlcNAc(Fuc)-GalNAz, wherein * denotes the attachment to the rest of the modified B7-H4 antibody.

[0179] In some embodiments, the steps of the deglycosylation / trimming step and the formation of the modified B7-H4 antibody are conducted sequentially.

[0180] In some embodiments, the steps of the deglycosylation / trimming step and the formation of the modified B7-H4 antibody are conducted simultaneously.

[0181] In some embodiments, the process for the preparation of a modified B7-H4 antibody is performed in a suitable buffer solution, e.g., buffered saline (e.g. phosphate- buffered saline, Tris-Attorney Docket No.43704-02721 MRSN-047 / 001WO buffered saline), citrate, HEPES, Tris and glycine. In some embodiments, the buffer solution is phosphate-buffered saline (PBS) or Tris buffered saline. In some embodiments, the buffer solution is phosphate-buffered saline (PBS).

[0182] In some embodiments, the process is performed at a temperature ranging from about 4 to about 50 °C. In some embodiments, the process is performed at a temperature ranging from about 10 to about 45 °C. In some embodiments, the process is performed at a temperature ranging from about 20 to about 40 °C. In some embodiments, the process is performed at a temperature ranging from about 30 to about 37 °C. In some embodiments, the process is performed at a temperature of about 30 °C. In some embodiments, the process is performed at a temperature of 30 °C.

[0183] In some embodiments, the process is performed at a pH value ranging from about 5 to about 9 (e.g., from about 5.5 to about 8.5, from about 6 to about 8, or from about 7 to about 8). In some embodiments, the process is performed at a pH value of about 7.4.

[0184] In some embodiments, the process for the preparation of a modified B7-H4 antibody comprises:(a) contacting a glycoprotein (e.g., a B7-H4 antibody glycan) comprising a B7-H4 antibody and core-GlcNAc moiety connected to site N297 of the antibody (according to EU numbering), with endoglycosidase Endo SH, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and(b) contacting the intermediate antibody with 4-AzGalNAc-UDP m the presence of a P-(l,4)-GalNAcT enzyme, thereby forming the modified B7-H4 antibody comprising the modified-GlcNAc moiety;wherein steps (a) and (b) are conducted concurrently.

[0185] In some embodiments, the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag resulting in an overall molecular weight of 139 kDa.

[0186] In some embodiments, the P-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag and has an overall molecular weight of 45.7 kDa, In some embodiments, the p-(l,4)-GalNAcT enzyme comprises an N-terminal 6xHis tag is derived from Trichopulsia m.

[0187] In some embodiments, the process is conducted in PBS buffer at pH value of about 7,4 and at a temperature of about 30 °C.Attorney Docket No.43704-02721 MRSN-047 / 001WOB7-H4-Targeted Antibody-Drug Conjugates

[0188] The invention pertains to therapies involving immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a toxin e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), via site specific conjugation,

[0189] In embodiments, the B7-H4-targeted antibody drug conjugates described herein comprise a B7-H4 antibody or B7-II4 modified antibody as described herein.

[0190] In embodiments, the B7-H4-targeted antibody-drug conjugate is emiltatug ledadotin (also known as XMT-1660).

[0191] The conjugate described herein is a B7-H4-targeted antibody-drug conjugate comprising a B7-I I4 modified antibody and two molecules of a fully synthetic macromolecular linker-payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA). The fully synthetic macromolecular linker-payload is conjugated to the modified B7-H4 antibody m a site-specific manner enabled by glycan remodeling of the antibody at the asparagine group at position 297 of the antibody according to EU numbering.

[0192] In some embodiments, the B7-H4-targeted antibody-drug conjugate comprises a microtubule inhibitor payload. In some embodiments, the microtubule inhibitor payload is Monomethyl auristatin E (MMAE), Monomethyl auristatin F (MMAF) or AF-HPA.

[0193] In some embodiments, the B7-H4-targeted antibody-drug conjugate that comprises a microtubule inhibitor payload is felmetatug vedotm. In embodiments, the B7-H4-targeted antibodydrug conjugate that comprises a microtubule inhibitor payload is LNCB74.

[0194] The average drug-to-antibody ratio (DAR) of the B7-H4-targeted antibody-drug conjugate is about 6. In some embodiments, the DAR of B7-H4-targeted antibody-drug conjugate is about 2 to about 8. In some embodiments, the DAR of B7-H4-targeted antibody-drug conjugate is about 5 to about 7. In some embodiments, the DAR of B7-H4-targeted antibody-drug conjugate is about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2 about 6.3, about 6.4, or about 6.5, or any number in between.

[0195] In some embodiments, the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):Attorney Docket No.43704-02721 MRSN-047 / 001WO(I) whereini. d is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7);iii. the drug is attached to the antibody at position 297, e.g,, of the heavy chain, when numbered in accordance with EU numbering via a linker moiety;iv. ■is GlcNAc; is Fuc; andD is GalNAc,Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0196] In some embodiments, dis can be from about 1 to about 3. In some embodiments, dis can be about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5,

[0197] GlcNAc refers to N-acetylglucosamine (i.e., p-D-(Acetylammo)-2-deoxy-glucopyranose or N-Acetyl-D-glucosamine).

[0198] Fuc refers to fucose (i.e,, (2S,3R,4R,5S)-6-Methyltetrahydro-2H-pyran-2, 3,4,5-tetraol or 6-Deoxy-l-galactose).

[0199] GalNAc refers to N-acetylgalactosamine (i.e., 2-(Acetylamino)-2-deoxy-D-galactose, 2-Acetamido-2-deoxy-D-galactose, N-Acetylchondrosamine, 2-Acetamido-2-deoxy-D-galactopyranose, or N-Acetyl-D-galactosamine).

[0200] In some embodiments, the GlcNAc is bonded to the conjugate through a reactive moiety of GlcNAc.

[0201] In some embodiments, the Fuc is bonded to the conjugate through a reactive moiety of Fuc.

[0202] In some embodiments, the GalNAc is bonded to the conjugate through a reactive moiety of GalNAc.

[0203] In some embodiments, the drug (e.g., drug-linker moiety) is attached to the antibody at position N180 of SEQ NO: 11, a position corresponding to N297 (as numbered by EU numbering).

[0204] In some embodiments the drug (e.g., drug-linker moiety) is attached to the antibody at a position corresponding to N180 of SEQ ID NO: 11. Corresponding positions are determined, for example, using a sequence alignment tool.

[0205] In some embodiments, the drug (e.g., drug-linker moiety) is attached to the antibody at position N296 of SEQ NO: 13, a position corresponding to N297 (as numbered by EU numbering).

[0206] In some embodiments, the drug (e.g., drug-linker moiety) is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 14. In some embodiments, the drug (e.g., drug¬ linker moiety) is attached to the antibody at a position corresponding to N296 of SEQ ID NO: 13. Corresponding positions are determined, for example, using a sequence alignment tool.

[0207] In some embodiments, the antibody comprises a light chain variable region comprising SEQ ID NO: 8 and a heavy chain variable region comprising SEQ ID NO: 9.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0208] In some embodiments, the antibody comprises a light chain comprising SEQ ID NO: 12 and a heavy chain comprising SEQ ID NO: 14.

[0209] In some embodiments, the antibody comprises a light chain comprising SEQ ID NO: 12 and a heavy chain comprising SEQ ID NO: 13.

[0210] In some embodiments, the B7-H4-targeted antibody-drug conjugate is XMT-1660.

[0211] In some embodiments the B7-H4-targeted antibody-drug conjugate that comprises a microtubule inhibitor is emiltatug ledadotin.

[0212] In some embodiments, the process for the preparation of a modified B7-H4 antibody comprises:(a) contacting a glycoprotein (e.g., a B7-H4 antibody glycan) comprising a B7-H4 antibody and core-GlcNAc moiety connected to site N297 (according to EU numbering) of the antibody, with endoglycosidase Endo SEI, thereby forming an intermediate antibody comprising a terminal GlcNAc moiety; and(b) contacting the intermediate antibody with 4-AzGalNAc-UDP in the presence of a Q-(l,4)-GalNAcT enzyme, thereby forming the modified B7-H4 antibody comprising the modified-Glc Ac moiety;wherein steps (a) and (b) are conducted concurrently.

[0213] In some embodiments, the endoglycosidase is Endo SH, a fusion between the two endoglycosidases, Endo S and Endo H, linked by a Gly-rich spacer comprising an internal 6xHis tag resulting in an overall molecular weight of 139 kDa.

[0214] In some embodiments, the P~(l,4)-GalNAcT enzyme comprises an N-temiinal 6xHis tag and has an overall molecular weight of 45.7 kDa. In some embodiments, the P-(l,4)-GalNAcT enzyme comprises an N-temiinal 6xHis tag is derived from Trichopulsia ni.

[0215] In some embodiments, the process is conducted in PBS buffer at pH value of about 7.4 and at a temperature of about 30 °C.

[0216] The B7-H4-targeted antibody-drug conjugate, (e.g., XMT-1660) suitable for use in the methods disclosed herein can be generated and purified by well-known techniques e.g., WO 2018098269 and US 17 / 568,378, each of which is incorporated herein in its entirety by reference.

[0217] In some embodiments, the B7-H4-targeted antibody-drug conjugate of Formula (I) is of Formula (I-a):Attorney Docket No.43704-02721 MRSN-047 / 001WOdis is about 2.

[0218] In some embodiments, the B7-H4-targeted antibody-drug conjugate of Formula (I) is of Formula (I-b):Attorney Docket No.43704-02721 MRSN-047 / 001WOwherein ■ is GlcNAc; anddi3 is about 2.

[0219] In some embodiments, the B7-H4-targeted antibody-drug conjugate of Formula (I) is of Formula (I-c):Attorney Docket No.43704-02721 MRSN-047 / 001WOdis is about 2.

[0220] In some embodiments, the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (TA):Attorney Docket No.43704-02721 MRSN-047 / 001WO(IA).

[0221] The conjugate described herein is a B7-H4-targeted antibody-drug conjugate comprising a B7-H4 modified antibody and two molecules of a fully synthetic macromolecular linker-payload bearing three copies of the microtubule inhibitor auristatin F-hydroxypropyl amide (AF-HPA). In some embodiments, the free auristatin payload, auristatin F hydroxypropyl amide (AF-HPA) comprises:

[0222] In some embodiments, the primary AF-HPA metabolite, Auristatin F (AF),Methods of TreatmentAttorney Docket No.43704-02721 MRSN-047 / 001WO Treatment of Cancer

[0223] The disclosure provides a method of treating cancer by administering to a subject m need thereof an effective amount of the B7-H4-targeted antibody-drug conjugate as described herein.

[0224] The disclosure provides a method of treating a solid tumor by administering to a subject in need thereof an effective amount of the B7-H4-targeted antibody-drug conjugate as described herein.

[0225] The disclosure provides a method of treating cancer, such as adenoid cystic carcinoma (ACC), biliary tract cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, hematological cancer, endometrial cancer, fallopian tube cancer, primary peritoneal cancer, cholangiocarcinoma, NSCLC (squamous and / or adenocarcinoma), gastrointestinal cancer such as gastric cancer and colorectal cancer, and lung cancer, for example, wherein the cancer is ACC, breast cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, or primary peritoneal cancer, by administering to a subject m need thereof an effective amount of the B7-H4-targeted antibody-drug conjugate as described herein.

[0226] The disclosure provides a method of treating adenoid cystic carcinoma (ACC) by administering to a subject in need thereof an effective amount of the B7-H4-targeted antibody-drug conjugate as described herein.

[0227] ACC is a cancer that can be found m many anatomic sites including, the salivary gland, breast, lacrimal gland, lung, brain, Bartholin gland, trachea, and the paranasal sinuses. ACC is most commonly found in the salivary' gland. ACC is the third-most common malignant salivary’ gland tumor overall (after mucoepidermoid carcinoma and polymorphous adenocarcinoma) and represents 28% of malignant submandibular gland tumors, making it the single most common malignant salivary' gland tumor in this region.

[0228] Patients with solid tumors including adenoid cystic carcinoma are administered a B7-H4-targeted antibody-drug conjugate (e.g. as described herein, e.g., XMT-1660) in an amount sufficient to exert a therapeutically useful effect.

[0229] In embodiments, the AAC is ACC Type I (ACC-I). In embodiments, the ACC is ACC Type II (ACC-II).

[0230] In embodiments, the subject having ACC is identified for treatment by (a) identification of an activating mutation a Notch pathway gene (e.g., NOTCH- 1, NOTCH-2,Attorney Docket No.43704-02721 MRSN-047 / 001WO NOTCH-3, or NOTCH-4), optionally in the NOTCH-1 gene, optionally as identified by next¬ generation sequencing (NGS); and / or (b) a tumor biopsy testing positive for c-MYC and negative or low-expressing for TP63, optionally as measured by immunohistochemistry (IHC).

[0231] In some embodiments, the subject with ACC is identified for treatment by having a clinical course characterized by <3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with atypical sites of metastases (e.g. bone, CNS, and non-pulmonary or -hepatic viscera) and a solid tumor morphology on histologic evaluation.

[0232] In embodiments the ACC (e.g., tumor cells of the ACC) is positive for B7-H4 expression. In embodiments, the ACC (e.g., tumor cells of the ACC) is positive for B7-H4 as determined by a B7-H4 TPS score of greater than or equal to 50%, as determined by the methods described herein.Treatment of cancer that is resistant to Topoisomerase- 1 inhibitor treatment

[0233] Recent studies have shown that patients treated sequentially with ADCs that include a topoisomerase- 1 (TOPO-1) inhibitor payload become resistant, with significantly decreased progression-free survival (PF'S) times following administration of the second TOPO-1 inhibitor¬ containing ADC when compared to PFS times following administration of the first TOPO-1 inhibitor-containing ADC (AbelmanR. O., etal., J. Clin. Oncology, 41(16 suppl), 2023, doi.org / 10.1200 / JC0.2023.41.16 suppl.102, incorporated herein by reference in its entirety).Without being bound by theory, it is hypothesized that this resistance is mediated by resistance to the TOPO-1 inhibitor payload. There thus exists a need for ADC therapeutics which are effective in cancers which have become resistant to treatment with TOPO-1 inhibitor chemotherapies and / or TOPO-1 inhibitor-containing ADCs, and which can be administered in combination with such chemotherapy regimens comprising TOPO-1 inhibitors or TOPO-1 inhibitor-containing ADCs due to, for example, differences in their mechanism of action, clearance pathways, and safety profiles.

[0234] As used herein, the term “Topoisomerase 1 inhibitor-containing antibody drug conjugate” refers to a molecule (e.g., ADC) that includes a protein based recognition molecule (PBRM; e.g. an antibody) and a topoisomerase 1 inhibitor payload. Topoisomerase 1 inhibitors include, for example, camptothecin, camptothecin derivatives, camptothecin analogs and nonnatural camptothecins, CPT-l l (irinotecan), SN-38, GI-147211C, topotecan, 9-aminocamptothecm, 7-hydroxymethyl camptothecin, 7-aminomethyl camptothecin, 10-hydroxycamptothecin, (20S)-Attorney Docket No. 43704-02721 MRSN-047 / 001WO camptothecin, rubitecan, gimatecan, karenitecin, silatecan, lurtotecan, exatecan, diflomotecan, belotecan, lurtotecan and S39625, Other exemplary7TOPO-1 inhibitor compounds are described in, for example, J. Med. Chem., 29:2358-2363 (1986); J. Med. Chem., 23:554 (1980); J. Med. Chem., 30:1774 (1987) (incorporated herein by reference). Exemplary topoisomerase 1 inhibitor chemotherapies include chemotherapy regimens that include irinotecan (e.g., Onivyde or Camptosan) or topotecan (e.g., Hycamtin). Exemplary topoisomerase 1 inhibitor-containing antibody drug conjugates include ENHERTU™ and TRODELVY™. Additional exemplary topoisomerase 1 inhibitors and topoisomerase 1 inhibitor- containing antibody drug conjugates are described in, for example, WO2010 / 093395, W02020 / 059772, WO2014 / 057687, WO2014 / 061277, WO2022 / 253284, W02020 / 063676, WO2022 / 068898, WO2021 / 115426, W02021 / 121204, WO2021 / 139758, W02023 / 001248, WO2022 / 078425, WO2022 / 228406, WO2023 / 109965, WO2019 / 114666, WO2023 / 143154, WO2021 / 228141, WO2020 / 244657, WO2021 / 249228, WO2023 / 280227, W02023 / 006084, WO2022 / 126593, WO2020 / 259258, WO2023 / 186015, WO2022 / 161479, WO2023 / 143208, WO2023 / 143263, WO2023 / 170216, WO2023 / 083846, WO2023 / 178289, WO2023 / 174213, WO2023 / 178452, the contents of which are incorporated herein by reference in their entirety.

[0235] Accordingly, disclosed herein is a method of treating cancer comprising administering an ADC as described herein (e.g., a B7-H4-targeted ADC comprising a microtubule inhibitor such as, for example, felmetatug vedotin, LNCB74 or an ADC described in WO2023 / 056362, or XMT-1660, administered as described herein) in a subject in need thereof, wherein the subject has received prior therapy comprising a topoisomerase 1 inhibitor (e.g., a prior chemotherapy regimen comprising a topoisomerase 1 inhibitor). In embodiments, the cancer has become resistant to or not responsive to therapy with the topoisomerase 1 inhibitor (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor). In embodiments, the cancer has progressed following therapy with the topoisomerase 1 inhibitor (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor) but prior to administration of the B7-H4-targeted antibody drug conjugate. In some embodiments, a patient who has become resistant or not responsive to treatment with a topoisomerase 1 inhibitor (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor) exhibits a decrease in tumor response following one or more doses of a topoisomerase 1 inhibitor (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor) relative to the tumor response following one or more earlier doses of a topoisomerase 1 inhibitorAttorney Docket No.43704-02721 MRSN-047 / 001WO (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor). In some embodiments, a tumor which initially responds to therapy which includes topoisomerase 1 inhibitor (e.g,, a chemotherapy regimen comprising a topoisomerase 1 inhibitor) experiences progressive disease following one or more subsequent doses of a topoisomerase 1 inhibitor (e.g., a chemotherapy regimen comprising a topoisomerase 1 inhibitor).

[0236] In embodiments, the topoisomerase 1 inhibitor is irinotecan (e.g,, Onivyde or Camptosan). In embodiments, the topoisomerase 1 inhibitor is topotecan (Hycamtin). In embodiments the treatment with a topoisomerase 1 inhibitor comprises a regimen that includes a topoisomerase 1 inhibitor (e.g., irinotecan and / or topotecan) and one or more additional chemotherapeutic agents.

[0237] Accordingly, disclosed herein is a method of treating cancer comprising administering an ADC as described herein (e.g., a B7-H4-targeted ADC comprising a microtubule inhibitor such as, for example, felmetatug vedotin, LNCB74 or an ADC described in WO2023 / 056362, or XMT-1660, administered as described herein) in a subject in need thereof, wherein the subject has received prior therapy comprising a topoisomerase 1 inhibitor- containing antibody drug conjugate. In embodiments, the cancer has become resistant to or not responsive to therapy with the topoisomerase 1 inhibitor- containing antibody drug conjugate. In embodiments, the resistance is caused by resistance to the topoisomerase 1 inhibitor. In embodiments, the cancer has progressed following therapy with the topoisomerase 1 inhibitor-containing antibody drug conjugate but prior to administration of the B7-H4-targeted antibody drug conjugate. In some embodiments, a patient who has become resistant or not responsive to treatment with a topoisomerase 1 inhibitor-containing antibody drug conjugate exhibits a decrease in tumor response following one or more doses of TOPO-1 inhibitor- containing ADCs relative to the tumor response following one or more earlier doses of TOPO-1 inhibitor-containing ADCs. In some embodiments, a tumor which initially responds to therapy which includes a TOPO-1 inhibitor-containing ADC experiences progressive disease following one or more subsequent doses of a TOPO-1 inhibitor¬ containing ADC.

[0238] In embodiments, the prior topoisomerase 1 inhibitor-containing antibody drug conjugate targets an antigen different than the antigen targeted by the ADC described herein, for example, other than B7-H4. In embodiments, the topoisomerase 1 inhibitor-containing antibody drug conjugate targets HER2 or TROP2, for example, is ENHERTU or TRODELVY. InAttorney Docket No.43704-02721 MRSN-047 / 001WO embodiments, the prior topoisomerase 1 inhibitor-containing antibody drug conjugate targets B7-H4, for example, is AZD8025 (puxitatug samrotecan or other topoisomerase 1 inhibitor-ADC described in W02022 / 053650), HS-20089 (or other B7-H4-targeting ADC comprising a topoisomerase 1 inhibitor described in WO2020 / 244657), GSK5733584, or BG-C9074 (or a topoisomerase 1 inhibitor-containing antibody drug conjugate described in WO2022 / 068878).

[0239] In embodiments, the methods further include administering an immunomodulator, for example, an anti-PD-1 or anti-PD-Ll therapy, as described herein.

[0240] Accordingly, disclosed herein is a method of treating cancer comprising administering an ADC as described herein (e.g., a B7-H4 targeting / ADC comprising a microtubule inhibitor such as, for example, (I) felmetatug vedotin, or an ADC described in WO2023 / 056362, (2) LNCB74 or (3) XMT-1660, e.g., administered as described herein) in combination with a therapy comprising a topoisomerase I inhibitor (such as, for example, irinotecan or topotecan).

[0241] Accordingly, disclosed herein is a method of treating cancer comprising administering an ADC as described herein (e.g., a B7-H4 targeting ADC comprising a microtubule inhibitor such as, for example, (1 ) felmetatug vedotin, or an ADC described in WO2023 / 056362, (2) LNCB74 or (3) XMT-1660, e.g., administered as described herein) in combination with a therapy comprising a topoisomerase 1 inhibitor- containing antibody drug conjugate. In embodiments, the prior topoisomerase 1 inhibitor-containing antibody drug conjugate targets an antigen different than the antigen targeted by the ADC described herein, for example, other than B7-H4. In embodiments, the topoisomerase 1 inhibitor-containing antibody drug conjugate targets HER2 or TROP2, for example, is ENHERTU or TRODELVY In embodiments, the prior topoisomerase 1 inhibitor-containing antibody drug conjugate targets B7-H4, for example, is AZD8025 (puxitatug samrotecan or other topoisomerase 1 inhibitor-ADC described in W02022 / 053650), HS-20089 (or other B7-H4-targeting ADC comprising a topoisomerase 1 inhibitor described in WO2020 / 244657), GSK5733584, or BG-C9074 (or a topoisomerase 1 inhibitor-containing antibody drug conjugate described in WO2022 / 068878). In embodiments, the methods further include administering an immunomodulator, for example, an anti-PD-1 or anti-PD-Ll therapy, as described herein.Dosage and Administration

[0242] The cancer therapy provided herein, comprising a B7-H4-targeted antibody-drug conjugate (for example as described herein), is administered in an amount sufficient to exert aAttorney Docket No. 43704-02721 MRSN-047 / 001WO therapeutically useful effect. Typically, the active agents are administered in an amount that does not result in undesirable side effects of the patient being treated, or that minimizes or reduces the observed side effects. B7-H4-expressing cancers include for example, adenoid cystic carcinoma (ACC), breast cancer (e.g., triple negative breast cancer (TNBC), or HR+ / HER2- breast cancer), endometrial cancer, ovarian cancer, non-small cell lung cancer (e.g., squamous cell carcinoma), pancreatic cancer, thyroid cancer, kidney cancer (e.g,, renal cell carcinoma), bladder cancer (e.g., urothelial cell carcinoma), colon cancer, head and neck cancer, small cell lung cancer, gastric cancer, melanoma, bile duct carcinoma, uterine cancer, and cholangial carcinoma.

[0243] It is understood that the precise dosage and duration of treatment is a function of the tissue or tumor being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data and / or can be determined from known dosing regimens of the particular agent. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated, the weight of the individual, the route of administration and / or the extent or severity of the disease and other factors that are within the level of a skilled medical practitioner to consider. Generally, dosage regimens are chosen to limit toxicity. It should be noted that the attending physician would know how to and when to terminate, interrupt or adjust therapy to lower dosage due to toxicity, or bone marrow, liver or kidney or other tissue dysfunctions. Conversely, the attending physician would also know how to and when to adjust treatment to higher levels if the clinical response is not adequate (precluding toxic side effects). It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supendsing the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope thereof.

[0244] For example, the B7-H4-targeted antibody-drug conjugate, is administered in a therapeutically effective amount to decrease the tumor volume.

[0245] Patients with multiple solid tumors including ACC, breast, ovarian, and endometrial cancers are administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) in an amount sufficient to exert a therapeutically useful effect.

[0246] Patients with solid tumors including adenoid cystic carcinoma are administered a B7-H4-targeted antibody-drug conjugate (e g. XMT-1660) m an amount sufficient to exert a therapeutically useful effect.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0247] In some embodiments, the tumor or cancer is positive for B7-H4 expression.

[0248] In some embodiments, the subject has adenoid cystic carcinoma (ACC). ACC is a cancer that can be found in many anatomic sites including, the salivary gland, breast, lacrimal gland, lung, brain, Bartholin gland, trachea, and the paranasal sinuses. ACC is most commonly found in the salivary7gland. ACC is the third-most common malignant salivary gland tumor overall (after mucoepidermoid carcinoma and polymorphous adenocarcinoma) and represents 28% of malignant submandibular gland tumors, making it the single most common malignant salivary gland tumor in this region. In some embodiments, the ACC is ACC Type I. In some embodiments, the ACC is ACC Type II.

[0249] In some embodiments, the subject has triple negative breast cancer (TNBC). In some embodiments wherein the subject has TNBC, the TNBC status of the subject can be determined by American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines.

[0250] In some embodiments, the subject is a subject having breast cancer (e.g. TNBC) that was initially diagnosed as having HR+ breast cancer. In some embodiments, the HR+ status of the subject can be determined by ASCO / CAP guidelines.

[0251] In some embodiments the subject has HR+ / HER2- breast cancer. In some embodiments, the HER2- status of the subject can be indicated by a HER2 immunohistochemistry7(IHC) result of 0 or 1 or an IHC result of 2 combined with a negative fluorescence in-situ hybridization (FISH) result.

[0252] In some embodiments the subject has endometrial cancer.

[0253] In other embodiments, the subject has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0254] In some embodiments, the subject that has unresectable or recurrent / metastatic TNBC after standard chemotherapy. In some embodiments, the subject that has TNBC has received at least 1 line of systemic therapy in locally advanced or metastatic breast cancer setting. In some embodiments, the subject that has TNBC has received at least 2 lines of systemic therapy in locally advanced or metastatic breast cancer setting. In some embodiments, the patient has histologically or cytologically proven diagnosis of breast cancer with evidence of metastatic or locally advanced disease. In some embodiments, the patient has estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative tumor based on local testing on the most recent tumorAttorney Docket No. 43704-02721 MRSN-047 / 001WO biopsy. In some embodiments, the patient has received 1-3 prior lines of chemotherapy for metastatic setting. In some embodiments, the patient with BRCA mutation has received prior treatment with a PARP inhibitor.

[0255] In some embodiments, the subject has HR+ / HER2- breast cancer post-CDK4 / 6 inhibitor and endocrine-based therapy. In some embodiments, the subject that has HR+ / HER2-breast cancer has received at least one line of systemic therapy which must have included CDK 4 / 6 inhibitor and endocrine therapy (ET), in an advanced or metastatic breast cancer setting. In some embodiments the subject that has HR+ / HER2- breast cancer has histologically or cytologically proven diagnosis of breast cancer with evidence of metastatic or locally advanced disease. In some embodiments, the subject that has ER-positive and / or PR-positive tumor and HER2-negative tumor based on local testing on the most recent tumor biopsy.

[0256] In some embodiments, subjects having HR+ / HER2- breast cancer with tumor expression of both progesterone receptor and estrogen receptor >10% by IHC are required to receive CDK4 / 6 inhibitor and endocrine-based therapy.

[0257] In some embodiments, the subject that has advanced or metastatic breast cancer has received 1 to 4 prior lines of systemic therapy in a locally advanced or metastatic breast cancer setting, one of which must have included an approved ADC. Treatment in the neoadjuvant or adjuvant setting is not counted toward the prior lines of therapy. For participants with a breast cancer gene (BRCA) mutation, prior treatment with a poly (ADP-ribose) polymerase inhibitor (PARPi) is allowed and will not be counted toward prior lines of systemic therapy.

[0258] In some embodiments, the subject that has advanced or metastatic breast cancer has received at least 1 line of systemic therapy. Participants with tumor expression of both progesterone receptor and estrogen receptor >10% by IHC are required to have received prior therapy with a CDK4 / 6 inhibitor(s) (e.g. abemaciclib, palbociclib, and ribociclib)combined with ET in any setting.

[0259] In some embodiments, the subject that has advanced or metastatic breast cancer has not received more than 3 prior lines of chemotherapy (including ADCs) for advanced or metastatic disease. For participants with a BRCA mutation, prior treatment with a PARPi is allowed and will not be counted towards prior lines of chemotherapy.

[0260] In some embodiments, the subject that has endometrial cancer has received at least 1 line of systemic therapy including platinum-based chemotherapy for advanced or metastatic disease.Attorney Docket No. 43704-02721 MRSN-047 / 001WO In some embodiments, the subject has histologically or cytologically proven diagnosis of endometrial carcinoma, with evidence of metastatic or locally advanced disease who have no satisfactory treatment options and for whom experimental therapy is appropriate. In some embodiments, the subject has received at least 1 prior line of platinum-doublet chemotherapy and no more than 3 prior lines of systemic therapy for recurrent or metastatic cancer, not including hormonal therapy. In some embodiments, the subject that has endometrial cancer must not have endometrial sarcoma or carcinosarcoma.

[0261] In some embodiments, a subject having microsatellite instability (MSI) high tumors have received at least one line of therapy containing a PD-1 or a PD-L1 inhibitor.

[0262] In some embodiments, the subject that has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer has received at least 1 line of systemic therapy for advanced or metastatic disease, which should include platinum-based chemotherapy. In some embodiments, the subject that has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer has received at least 2 lines of systemic therapy for advanced or metastatic disease, which should include platinum-based chemotherapy. In some embodiments, the subject has a histological diagnosis of high grade serous ovarian cancer, which includes fallopian tube cancer, or primary peritoneal cancer, that is metastatic or recurrent. In some embodiments, the subject must have platinum-resistant recurrent disease, defined as completing 4 or more cycles of platinum- based therapy and radiographically progressing within 6 months of last platinum-based therapy. In some embodiments, the subject who has received 1 prior line of chemotherapy, must have achieved a complete or partial response to that therapy and their disease progressing between 3 and 6 months after the last dose of platinum in the first-line setting. In some embodiments, the subject who has received 2 to 4 prior lines of chemotherapy, disease progressing within less than or equal to 6 months after the last dose of platinum in the most recent chemotherapy. In some embodiments, the subject who has received 1 to 4 prior lines of systemic therapy for ovarian cancer including at least 1 prior line of a platinum- containing regimen.

[0263] In some embodiments, the subject has not received a vascular endothelial growth factor (VEGF)-targeted therapy. In some embodiments, the subject is not currently receiving a VEGF -targeted therapy. In some embodiments, the subject has not received a prior VEGF-targeted therapy.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0264] In some embodiments, the VEGF-targeted therapy can be any VEGF-targeted therapy known in the art. In some embodiments, the VEGF-targeted therapy comprises bevacizumab, pegaptamb, ranibizumab, aflibercept, conbercept, brolucizumab, or faricimab.,

[0265] In some embodiments, the subject does not have a history of proteinuria. In some embodiments, the subject does not have proteinuria. In some embodiments, the subject does not have a history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy. In some embodiments, the subject does not have grade 2 or higher proteinuria. In some embodiments, the subject does not have a history of grade 2 or higher proteinuria.

[0266] In some embodiments, the subject has or develops proteinuria as a result of treatment with XMT-1660. In some embodiments, the subject does not have and does not develop proteinuria as a result of treatment with XMT-1660. In some embodiments, the subject has or develops proteinuria as a result of treatment with XMT-1660 and has no history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy. In some embodiments, the subject has or develops proteinuria as a result of treatment with XMT-1660 and has a history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy. In some embodiments, the subject does not have and does not develop proteinuria as a result of treatment with XMT-1660 and has a history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy. In some embodiments, the subject does not have and does not develop proteinuria as a result of treatment with XMT-1660 and does not have a history’ of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy.

[0267] In some embodiments, the subject has a protein urine protein concentration of less than or equal to 500 mg within 14 days prior to administration of the B7-H4-targeted antibody-drug conjugate.

[0268] The disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an angiotensin converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB) and a B7-H4-targeted antibody-drug conjugate. In some embodiments, the subject is further administered a sodium-glucose co-transporter 2 (SGLT2) inhibitor.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0269] The disclosure provides a method of treating cancer in a subject, comprising administering to the subject a sodium-glucose co-transporter 2 (SGLT2) inhibitor and a B7-H4-targeted antibody-drug conjugate. In some embodiments, the subject is further administered an ACE inhibitor and / or an ARB.

[0270] In some embodiments, the ACE inhibitor, ARB and / or SGLT2 inhibitor reduce or prevent proteinuria in said subject.

[0271] The disclosure provides methods of decreasing the incidence or severity of proteinuria in a subject having cancer and receiving a B7-H4-targeted antibody-drug conjugate, comprising administering (a) an ACE inhibitor and / or an ARB and / or (b) a SGLT2 inhibitor.

[0272] In some embodiments, the SGLT2 inhibitor is any SGLT2 inhibitor known in the art. In some embodiments, the SGLT2 inhibitor is canagliflozin, dapagliflozin or empaglrflozin.

[0273] In some embodiments, the ARB is any ARB known in the art. In some embodiments, the ARB is azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan or valsartan. In some embodiments, the ARB is losartan.

[0274] In some embodiments, the ACE inhibitor is any ACE inhibitor known in the art. In some embodiments, the ACE inhibitor is benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

[0275] In some embodiments, the ACE inhibitor and / or ARB is administered at a dosage sufficient to restore normal blood pressure in the subject. In some embodiments, the ACE inhibitor and / or ARB is titrated to normal blood pressure.

[0276] In some embodiments, losartan is administered at a therapeutically effective dosage. In some embodiments, losartan is administered at a dosage sufficient to restore normal blood pressure in the subject. In some embodiments, the ACE inhibitor and / or ARB is administered one daily, every other day, once weekly, or any dosing schedule in between. In some embodiments, the ACE inhibitor and / or ARB is administered as a one time administration. In some embodiments, the ACE inhibitor and / or ARB is administered daily.

[0277] In some embodiments, losartan is administered at a dosage of about 10 mg to about 1000 mg. In some embodiments, losartan is administered at a dosage of about 25 mg to 100 mg. In some embodiments, losartan is administered at a dosage of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,Attorney Docket No.43704-02721 MRSN-047 / 001WO about 100 mg, or any dosage m between. In some embodiments, losartan is administered at a dosage of about 25 mg to 100 mg once daily. In some embodiments, losartan is administered at a dosage of about 25 mg once daily.

[0278] In some embodiments, the ARB and or ACE inhibitor is initiated prior to the first administration of the B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660).

[0279] In some embodiments, the subject having ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is administered by infusion, a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount according to body surface area (BSA). The BSA adjusted dose will be calculated when possible, using the Mosteller Formula. The starting dose will be calculated based on height and weight collected within 14 days of the first dose (can be collected the day of first dose). Dose calculations in subsequent cycles will be made for weight changes >5% from the most recent dose calculation. Dose adjustments based on subsequent weight measurements will be made. Additional weight measurements will be obtained and BSA confirmed or altered prior to dosing at Cycle 2 and every 2 cycles thereafter.

[0280] In some embodiments, administration of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is via infusion. Methods of infusion can comprise any method of infusing therapeutic agents to a subject known in the art. In some embodiments the infusion is an intravenous (IV) infusion.

[0281] In some embodiments, infusions of a B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) occur over a duration of at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 60 minutes, at least 65 minutes, at least 70 minutes, at least 75 minutes, at least 80 minutes, at least 85 minutes, at least 90 minutes, at least 95 minutes, at least 100 minutes, at least 105 minutes, at least 110 minutes, at least 115 minutes, at least 120 minutes, or any number of minutes therebetween. In some embodiments, the duration of infusion can be varied from the first infusion to the second and subsequent infusions.

[0282] In some embodiments, the initial dose of a B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) for each subject will be administered over 90 ±10 minutes. If no infusion related reactions occur, all subsequent doses can be administered over 60 ±10 minutes.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0283] In some embodiments, the subject having ACC, TNBC, HRT / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is administered by infusion a B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at a dosage amount that is between about 5 mg / m2to about 117 mg / m2.

[0284] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is between about 5 mg / m2to about 60 mg / m² or about 50 mg / m² to about 117 mg / m2.

[0285] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is between about 44.5 mg / m2to about 115.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is between 44.5 mg / m2to 115.0 mg / m2.

[0286] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, I IR-t BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 44.5 mg / m2on day 1 and on day 8 of a 4-week cycle.

[0287] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HRT BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 67.4 mg / m2once every 3 weeks.

[0288] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HRT BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 67.4 mg / m2once every 4 weeks.

[0289] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HRT BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 80.0 mg / m2once every 3 weeks.

[0290] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HRT BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g,, emiltatug ledadotin) at a dose of about 80.0 mg / m2once every 4 weeks.

[0291] In some embodiments, provided herein is a method of treating cancer, e.g,, ACC, TNBC, HRT BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targetedAttorney Docket No.43704-02721 MRSN-047 / 001WO antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 95.0 mg / m2once every 3 weeks.

[0292] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HR+ BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 95.0 mg / m2once every 4 weeks.

[0293] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HR+ BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 115.0 mg / m2once every 3 weeks.

[0294] In some embodiments, provided herein is a method of treating cancer, e.g., ACC, TNBC, HR+ BC, ovarian cancer or endometrial cancer, comprising administering a B7-H4-targeted antibody drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) at a dose of about 115.0 mg / m2once every 4 weeks.

[0295] In some embodiments, the dose is between about 5 mg / m2to about 10 mg / m2, about 10 mg / m2to about 15 mg / m2, about 15 mg / m2to about 20 mg / m2, about 20 mg / m2to about 25 mg / m2, about 25 mg / m2to about 30 mg / m2, about 30 mg / m2to about 35 mg / m2, about 35 mg / m2to about 40 mg / m2, about 40 mg / m2to about 45 mg / m2, about 45 mg / m2to about 50 mg / m2, about 50 mg / m2to about 55 mg / m2, about 55 mg / m2to about 60 mg / m2, about 60 mg / m2to about 65 mg / m2, about 65 mg / m2to about 70 mg / m2, about 75 mg / m2to about 80 mg / m2, about 85 mg / m2to about 90 mg / m2, about 90 mg / m2to about 95 mg / m2, about 95 mg / m2to about 100 mg / m2, or about 113.0 mg / m2to about 117.0 mg / m2.

[0296] In some embodiments, the B7-H4-targeted antibody-drug conjugate is administered at a dose of: about 28.2 mg / m2to about 29.2 mg / m2, about 32.9 mg / m2to about 33.9 mg / m2, about 37.6 mg / m2to about 38.6 mg / m2, about 44.0 mg / m2to about 45.0 mg / m2, about 50.2 mg / m2to about 51.2 mg / m2, about 58.5 mg / m2to about 59.5 mg / m2, about 66.9 mg / m2to about 67.9 mg / m2, about 77.0 mg / m2to about 78.0 mg / m2, about 79.5 mg / m2to about 80.5 mg / m2, about 87.1 mg / m2to about 88.1 mg / m2, about 94.5 mg / m2to about 95.5 mg / m2, or about 114.5 mg / m2to about 115.5 mg / m2.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0297] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 6,0 mg / m2to about 8.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 6.7 mg / m2to about 7.7 mg / m2. In some aspects, the dosage is about 6,0 mg / m2, about 6.1 mg / m2, about 6.2 mg / m2, about 6.3 mg / m2, about 6.4 mg / m2, about 6,5 mg / m2, about 6.6 mg / m2, about 6.7 mg / m2, about 6.8 mg / m2, about 6.9 mg / m2, about 7.0 mg / m2, about 7,1 mg / m2, about 7.2 mg / m2, about 7.3 mg / m2, about 7.4 mg / m2, about 7.5 mg / m2, about 7,6 mg / m2, about 7.7 mg / m2, about 7.8 mg / m2, about 7.9 mg / m2, or about 8.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 7.2 mg / m2.

[0298] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 12.0 mg / m2to about 15.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 13.9 mg / m2to about 14.9 mg / m2. In some aspects, the dosage is about 13.0 mg / m2, about 13.1 mg / m2, about 13.2 mg / m2, about 13.3 mg / m2, about 13.4 mg / m2, about 13.5 mg / m2, about 13.6 mg / m2, about 13.7 mg / m2, about 13.8 mg / m2, about 13.9 mg / m2, about 14.0 mg / m2, about 14.1 mg / m2, about 14.2 mg / m2, about 14.3 mg / m2, about 14.4 mg / m2, about 14.5 mg / m2, about 14.6 mg / m2, about 14.7 mg / m2, about 14.8 mg / m2, about 14.9 mg / m2, or about 15.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 14.4 mg / m2.

[0299] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 20.0 mg / m2to about 23.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 21.1 mg / m2to about 22.1 mg / m2. In some aspects, the dosage is about 20.0 mg / m2, about 20.1 mg / m2, about 20.2 mg / m2, about 20.3 mg / m2, about 20.4 mg / m2, about 20.5 mg / m2, about 20.6 mg / m2, about 20.7 mg / m2, about 20.8 mg / m2, about 20.9 mg / m2, about 21.0 mg / m2, about 21.1 mg / m2, about 21.2 mg / m2, about 21.3 mg / m2, about 21.4 mg / m2, about 21.5 mg / m2, about 21.6 mg / m2, about 21.7 mg / m2, about 21.8 mg / m2, about 21.9 mg / m2, about 22.0 mg / m2, about 22.1 mg / m2, about 22.2 mg / m2, about 22.3 mg / m2, about 22.4 mg / m2, about 22.5 mg / m2, about 22.6 mg / m2, about 22.7 mg / m2, about 22.8 mg / m2, about 22.9 mg / m2, or about 23.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 21.6 mg / m2.

[0300] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 23.5 mg / m2to about 27.0 mg / m2In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 24.65 mg / m2to about 25.65 mg / m2. In some aspects, the dosage isAttorney Docket No.43704-02721 MRSN-047 / 001WO about 23.5 mg / m2, about 23.6 mg / m2, about 23.7 mg / m2, about 23.8 mg / m2, about 23.9 mg / m2, about 24.0 mg / m2, about 24.1 mg / m2, about 24.2 mg / m2, about 24.3 mg / m2, about 24.4 mg / m2, about 24.5 mg / m2, about 24,6 mg / m2, about 24.65 mg / m2, about 24.7 mg / m2, about 24.8 mg / m2, about 24.9 mg / m2, about 25.0 mg / m2, about 25.1 mg / m2, about 25.11 mg / m2, about 25.12 mg / m2, about 25.13 mg / m2, about 25,14 mg / m2, about 25.15 mg / m2, about 25,16 mg / m2, about 25.17 mg / m2, about 25.18 mg / m2, about 25.19 mg / m2, about 25.2 mg / m2, about 25.3 mg / m2, about 25,4 mg / m2, about 25.5 mg / m2, about 25.6 mg / m2, about 25.65 mg / m2, about 25.7 mg / m2, about 25.8 mg / m2, about 25.9 mg / m2, about 26.0 mg / m2, about 26.1 mg / m2, about 26.2 mg / m2, about 26.3 mg / m2, about 26.4 mg / m2,, about 26.4 mg / m2, about 26.4 mg / m2, about 26.4 mg / m2, about 26.4 mg / m2, about 26.4 mg / m2or about 27.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 25.15 mg / m2.

[0301] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 27.0 mg / m2to about 30.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 28.2 mg / m2to about 29.2 mg / m2. In some aspects, the dosage is about 27.0 mg / m2, about 27.1 mg / m2, about 27.2 mg / m2, about 27.3 mg / m2, about 27.4 mg / m2, about 27.5 mg / m2, about 27.6 mg / m2, about 27.7 mg / m2, about 27.8 mg / m2, about 27.9 mg / m2, about 28.0 mg / m2, about 28.1 mg / m2, about 28.2 mg / m2, about 28.3 mg / m2, about 28.4 mg / m2, about 28.5 mg / m2, about 28.6 mg / m2, about 28.7 mg / m2, about 28.8 mg / m2, about 28.9 mg / m2, about 29.0 mg / m2, about 29.1 mg / m2, about 29.2 mg / m2, about 29.3 mg / m2, about 29.4 mg / m2, about 29.5 mg / m2, about 29.6 mg / m2, about 29.7 mg / m2, about 29.8 mg / m2, about 29.9 mg / m2, or about 30.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 28.7 mg / m2.

[0302] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 32.5 mg / m2to about 34.5 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 32.9 mg / m2to about 33.9 mg / m2. In some aspects, the dosage is about 32.5 mg / m2, about 32.6 mg / m2, about 32.7 mg / m2, about 32.8 mg / m2, about 32.9 mg / m2, about 33.0 mg / m2, about 33.1 mg / m2, about 33.2 mg / m2, about 33.3 mg / m2, about 33.4 mg / m2, about 33.5 mg / m2, about 33,6 mg / m2, about 33.7 mg / m2, about 33,8 mg / m2, about 33.9 mg / m2, about 34.0 mg / m2, about 34.1 mg / m2, about 34.2 mg / m2, about 34.3 mg / m2, about 34.4 mg / m2, about 34.5 mg / m2, about 34,6 mg / m2, about 34.7 mg / m2, about 34,8 mg / m2, about 34.9 mg / m2, In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 33.4 mg / m2.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0303] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 36.0 mg / m2to about 40.0 mg / m2In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 37.6 mg / m2to about 38.6 mg / m2. In some aspects, the dosage is about 36.0 mg / m2, about 36.1 mg / m2, about 36.2 mg / m2, about 36.3 mg / m2, about 36,4 mg / m2, about 36.5 mg / m2, about 36,6 mg / m2, about 36.7 mg / m2, about 36,8 mg / m2, about 36.9 mg / m2, about 37.0 mg / m2, about 37.1 mg / m2, about 37.2 mg / m2, about 37.3 mg / m2, about 37.4 mg / m2, about 37.5 mg / m2, about 37.6 mg / m2, about 37.7 mg / m2, about 37.8 mg / m2, about 37.9 mg / m2, about 38.0 mg / m2, about 38.1 mg / m2, about 38.2 mg / m2, about 38.3 mg / m2, about 38.4 mg / m2, about 38.5 mg / m2, about 38.6 mg / m2, about 38.7 mg / m2, about 38.8 mg / m2, about 38.9 mg / m2, about 39.0 mg / m2, about 39.1 mg / m2, about 39.2 mg / m2, about 39.3 mg / m2, about 39.4 mg / m2, about 39.5 mg / m2, about 39.6 mg / m2, about 39.7 mg / m2, about 39.8 mg / m2, about 39.9 mg / m2, about 40.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 38.1 mg / m2.

[0304] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 43.0 mg / m2to about 46.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 44.0 mg / m2to about 45.0 mg / m2. In some aspects, the dosage is about 43.0 mg / m2, about 43.1 mg / m2, about 43.2 mg / m2, about 43.3 mg / m2, about 43.4 mg / m2, about 43.5 mg / m2, about 43.6 mg / m2, about 43.7 mg / m2, about 43.8 mg / m2, about 43.9 mg / m2, about 44.0 mg / m2, about 44.1 mg / m2, about 44.2 mg / m2, about 44.3 mg / m2, about 44.4 mg / m2, about 44.5 mg / m2, about 44.6 mg / m2, about 44.7 mg / m2, about 44.8 mg / m2, about 44.9 mg / m2, about 45.0 mg / m2, about 45.1 mg / m2, about 45.2 mg / m2, about 45.3 mg / m2, about 45.4 mg / m2, about 45.5 mg / m2, about 45.6 mg / m2, about 45.7 mg / m2, about 45.8 mg / m2, about 45.9 mg / m2, about 46.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 44.5 mg / m2.

[0305] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 49.0 mg / m2to about 52.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 50.2 mg / m2to about 51.2 mg / m2. In some aspects, the dosage is about 49.0 mg / m2, about 49,1 mg / m2, about 49.2 mg / m2, about 49,3 mg / m2, about 49.4 mg / m2, about 49.5 mg / m2, about 49.6 mg / m2, about 49.7 mg / m2, about 49.8 mg / m2, about 49,9 mg / m2, about 50.0 mg / m2, about 50,1 mg / m2, about 50.2 mg / m2, about 50,3 mg / m2, about 50.4 mg / m2, about 50.5 mg / m2, about 50.6 mg / m2, about 50.7 mg / m2, about 50.8 mg / m2, about 50,9 mg / m2.Attorney Docket No.43704-02721 MRSN-047 / 001WO about 51.0 mg / m2, about 51.1 mg / m2, about 51.2 mg / m2, about 51.3 mg / m2, about 51.4 mg / m2, about 51.5 mg / m2, about 51.6 mg / m2, about 51.7 mg / m2, about 51.8 mg / m2, about 51.9 mg / m2, or about 52.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 50.7 mg / m2.

[0306] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 57.5 mg / m2to about 60.5 mg / m2In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 57.5 mg / m2to about 57.6 mg / m2. In some aspects, the dosage is about 57.7 mg / m2, about 57.8 mg / m2, about 57.9 mg / m2, about 58.0 mg / m2, about 58.1 mg / m2, about 58.2 mg / m2, about 58.3 mg / m2, about 58.4 mg / m2, or about 58.5 mg / m2about 58.6 mg / m2, about 58.7 mg / m2, about 58.8 mg / m2, about 58.9 mg / m2, about 59.0 mg / m2, about 59.1 mg / m2about 59.2 mg / m2, about 59.3 mg / m2, about 59.4 mg / m2, about 59.5 mg / m2, about 59.6 mg / m2, about 59.7 mg / m2,, about 59.8 mg / m2, about 59.9 mg / m2about 60.0 mg / m2about 60.1 mg / m2, about 60.2 mg / m2, about 60.3 mg / m2, about 60.4 mg / m2, or about 60.5 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 59.0 mg / m2.

[0307] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 66.0 mg / m2to about 69.0 mg / m2In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 66.9 mg / m2to about 67.9 mg / m2. In some aspects, the dosage is about 66.0 mg / m2, about 66.1 mg / m2, about 66.2 mg / m2, about 66.3 mg / m2, about 66.4 mg / m2, about 66.5 mg / m2, about 66.6 mg / m2, about 66.7 mg / m2, about 66.8 mg / m2, about 66.9 mg / m2, about 67.0 mg / m2, about 67.1 mg / m2, about 67.2 mg / m2, about 67.3 mg / m2, about 67.4 mg / m2, about 67.5 mg / m2, about 67.6 mg / m2, about 67.7 mg / m2, about 67.8 mg / m2, about 67.9 mg / m2, about 68.0 mg / m2, about 68.1 mg / m2, about 68.2 mg / m2, about 68.3 mg / m2, about 68.4 mg / m2, about 68.5 mg / m2, about 68.6 mg / m2, about 68.7 mg / m2, about 68.8 mg / m2, about 68.9 mg / m2, or about 69.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 67.4 mg / m2.

[0308] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 76.0 mg / m2to about 79.0 mg / m2. In some embodiments, the dosage is about 76.0 mg / m2, about 76.1 mg / m2, about 76,2 mg / m2, about 76.3 mg / m2, about 76.4 mg / m2, about 76.5 mg / m2, about 76.6 mg / m2, about 76.7 mg / m2, about 76.8 mg / m2, about 76.9 mg / m2, about 77.0 mg / m2, about 77.1 mg / m2, about 77,2 mg / m2, about 77.3 mg / m2, about 77.4 mg / m2, about 77.5 mg / m2, about 77.6 mg / m2, about 77.7 mg / m2, about 77.8 mg / m2, about 77.9 mg / m2, about 78.0 mg / m2.Attorney Docket No. 43704-02721 MRSN-047 / 001WO about 78.1 mg / m2, about 78.2 mg / m2, about 78.3 mg / m2, about 78.4 mg / m2, about 78.5 mg / m2, about 78.6 mg / m2, about 78.7 mg / m2, about 78.8 mg / m2, about 78.9 mg / m2, or about 79.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 77.5 mg / m2.

[0309] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 79.0 mg / m2to about 81.0 mg / m2. In some embodiments, the dosage is about 79.0 mg / m2, about 79.1 mg / m2, about 79.2 mg / m2, about 79.3 mg / m2, about 79.4 mg / m2, about 79.5 mg / m2, about 79.6 mg / m2, about 79.7 mg / m2, about 79.8 mg / m2, about 79.9 mg / m2, about 80.0 mg / m2, about 80.1 mg / m2, about 80.2 mg / m2, about 80.3 mg / m2, about 80.4 mg / m2, about 80.5 mg / m2, about 80.6 mg / m2, about 80.7 mg / m2, about 80.8 mg / m2, about 80.9 mg / m2, about 81.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 80.0 mg / m2.

[0310] In some embodiments, the dosage of the B7-H4-targeted antibody -drug conjugate is about 86.0 mg / m2to about 89.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 87.1 mg / m2to about 88.1 mg / m2. In some aspects, the dosage is about 86.0 mg / m2, about 86.1 mg / m2, about 86.2 mg / m2, about 86.3 mg / m2, about 86.4 mg / m2, about 86.5 mg / m2, about 86.6 mg / m2, about 86.7 mg / m2, about 86.8 mg / m2, about 86.9 mg / m2, about 87.0 mg / m2, about 87.1 mg / m2, about 87.2 mg / m2, about 87.3 mg / m2, about 87.4 mg / m2, about 87.5 mg / m2, about 87.6 mg / m2, about 87.7 mg / m2, about 87.8 mg / m2, about 87.9 mg / m2, about 88.0 mg / m2, about 88.1 mg / m2, about 88.2 mg / m2, about 88.3 mg / m2, about 88.4 mg / m2, about 88.5 mg / m2, about 88.6 mg / m2, about 88.7 mg / m2, about 88.8 mg / m2, about 88.9 mg / m2, or about 89.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 87.6 mg / m2.

[0311] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 94.0 mg / m2to about 96.0 mg / m2. In some embodiments, the dosage is about 94.0 mg / m2, about 94.1 mg / m2, about 94.2 mg / m2, about 94.3 mg / m2, about 94.4 mg / m2, about 94.5 mg / m2, about 94.6 mg / m2, about 94.7 mg / m2, about 94.8 mg / m2, about 94.9 mg / m2, about 95.0 mg / m2, about 95.1 mg / m2, about 95.2 mg / m2, about 95.3 mg / m2, about 95.4 mg / m2, about 95.5 mg / m2, about 95.6 mg / m2, about 95.7 mg / m2, about 95.8 mg / m2, about 95.9 mg / m2, about 96.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 95.0 mg / m2.

[0312] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 114.0 mg / m2to about 116.0 mg / m2. In some embodiments, the dosage is about 114.0 mg / m2, about 114.1 mg / m2, about 114.2 mg / m2, about 114,3 mg / m2, about 114.4 mg / m2, about 114,5Attorney Docket No. 43704-02721 MRSN-047 / 001WO mg / m2, about 114.6 mg / m2, about 114.7 mg / m2, about 114.8 mg / m2, about 114.9 mg / m2, about 115.0 mg / m2, about 115.1 mg / m2, about 115,2 mg / m2, about 115.3 mg / m2, about 115.4 mg / m2, about 115.5 mg / m2, about 115.6mg / m2, about 115.7 mg / m2, about 115.8 mg / m2, about 115.9 mg / m2, about 116.0 mg / m2. In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 115.0 mg / m2.

[0313] In some embodiments, the dosage of the B7-H4-targeted antibody-drug conjugate is about 1.0 mg / m2, about 2.0 mg / m2, about 3.0 mg / m2, about 4.0 mg / m2, about 5.0 mg / m2, about 6.0 mg / m2, about 7.0 mg / m2, about 8.0 mg / m2, about 9.0 mg / m2, about 10.0 mg / m2, about 11.0 mg / m2, about 12.0 mg / m2, about 13.0 mg / m2, about 14.0 mg / m2, about 15.0 mg / m2, about 16.0 mg / m2, about 17.0 mg / m2, about 18.0 mg / m2, about 19.0 mg / m2, about 20.0 mg / m2, about 21.0 mg / m2, about 22.0 mg / m2, about 23.0 mg / m2, about 24.0 mg / m2, about 25.0 mg / m2, about 26.0 mg / m2, about 27.0 mg / m2, about 28.0 mg / m2, about 29.0 mg / m2, about 30.0 mg / m2, about 31.0 mg / m2, about 32.0 mg / m2, about 33.0 mg / m2, about 34.0 mg / m2, about 35.0 mg / m2about 36.0 mg / m2, about 37.0 mg / m2, about 38.0 mg / m2, about 39.0 mg / m2, about 40.0 mg / m2, about 41.0 mg / m2, about 42.0 mg / m2, about 43.0 mg / m2, about 44.0 mg / m2, about 45.0 mg / m2, about 46.0 mg / m2, about 47.0 mg / m2, about 48.0 mg / m2, about 49.0 mg / m2, about 50.0 mg / m2, about 51.0 mg / m2, about 52.0 mg / m2, about 53.0 mg / m2, about 54.0 mg / m2, about 55.0 mg / m2, about 56.0 mg / m2, about 57.0 mg / m2, about 58.0 mg / m2, about 59.0 mg / m2, about 60.0 mg / m2, about 61.0 mg / m2, about 62.0 mg / m2, about 63.0 mg / m2, about 64.0 mg / m2, about 65.0 mg / m2, about 66.0 mg / m2, about 67.0 mg / m2, about 68.0 mg / m2, about 69.0 mg / m2, about 70.0 mg / m2, about 71.0 mg / m2, about 72.0 mg / m2, about 73.0 mg / m2, about 74.0 mg / m2, about 75.0 mg / m2, about 76.0 mg / m2, about 77.0 mg / m2, about 78.0 mg / m2, about 79.0 mg / m2, about 80.0 mg / m2, about 81.0 mg / m2, about 82.0 mg / m2, about 83.0 mg / m2, about 84.0 mg / m2, about 85.0 mg / m2, about 86.0 mg / m2, about 87.0 mg / m2, about 88.0 mg / m2, about 89.0 mg / m2, about 90.0 mg / m2, about 91.0 mg / m2, about 92.0 mg / m2, about 93.0 mg / m2, about 94.0 mg / m2, about 95.0 mg / m2, about 96.0 mg / m2, about 97.0 mg / m2, about 98.0 mg / m2, about 99.0 mg / m2, about 100.0 mg / m2, about 101.0 mg / m2, about 102.0 mg / m2, about 103.0 mg / m2, about 104.0 mg / m2, about 105.0 mg / m2, about 106.0 mg / m2, about 107.0 mg / m2, about 108.0 mg / m2, about 109,0 mg / m2, about 110.0 mg / m2, about 111.0 mg / m2, about 112.0 mg / m2, about 113,0 mg / m2, about 114.0 mg / m2, about 115.0 mg / m2, about 116.0 mg / m2, about 117,0 mg / m2.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0314] In some embodiments, the subject is administered a B7-H4-targeted antibody-drug conjugate (e g. XMT-1660) as a total dose. In some aspects, the total dose is about 1 mg to about 100 mg. In some aspects, the total dose is about 10 mg to about 90 mg. In some aspects, the total dose is about 30 mg to about 90 mg. In some aspects, the total dose is about 50 mg to about 90 mg. In some aspects, the total dose is about 70 mg to about 90 mg. In some aspects, the total dose is about 80 mg to about 90 mg. In some aspects, the total dose is about 90 mg.

[0315] In some embodiments, if the calculation of the total dose of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) based on mg / m2dosing is greater than 90 mg, the subject is administered a dose of 90 mg.

[0316] In some embodiments, the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) as a total dose. In some aspects, the total dose is about 1 mg to about 100 mg. In some aspects, the total dose is about 10 mg to about 190 mg. In some aspects, the total dose is about 30 mg to about 190 mg. In some aspects, the total dose is about 50 mg to about 190 mg. In some aspects, the total dose is about 70 mg to about 190 mg. In some aspects, the total dose is about 80 mg to about 190 mg. In some aspects, the total dose is about 100 mg to about 190 mg. In some aspects, the total dose is about 120 mg to about 190 mg. In some aspects, the total dose is about 150 mg to about 190 mg. In some aspects, the total dose is about 170 mg to about 190 mg. In some aspects, the total dose is about 190 mg.

[0317] In some embodiments, if the calculation of the total dose of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) based on mg / m2dosing is greater than 190 mg, the subject is administered a dose of 190 mg.

[0318] In some embodiments if the subject’s body surface area is calculated to be greater than 2.0 m2, the total dose of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) administered to the subject is calculated based on a body surface area of about 2.0 m2.

[0319] In some embodiments, the subject having ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is administered by infusion a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 90.0 mg / m2, or between about 37.0 and about 115.0 mg / m2. In some embodiments, the subject having ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is administered by infusion a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosageAttorney Docket No.43704-02721 MRSN-047 / 001WO amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2. In some embodiments, the subject having ACC, TNBC, HR+ / HER2- breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer is administered by infusion a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 28.7 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 7.2 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody¬ drug conjugate (e.g. XMT-1660) is about 14.4 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 21.6 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 25.1 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 25.15 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 25.2 mg / m2. In other embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 28.7 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 33.4 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 38.1 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 44.5 mg / m2. In other embodiments, the dosage of a B7-H4-targeted antibody -drug conjugate (e.g. XMT-1660) is about 50.7 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 59.0 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 67.4 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 77.5 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 80.0 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 87.6 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 95.0 mg / m2. In some embodiments, the dosage of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) is about 115.0 mg / m2

[0320] In some embodiments, the dosage amounts are administered intravenously once every week (i.e,, 7-day cycle), once every two weeks (i.e., 14-day cycle), three weeks (i.e,, 21 -day cycle) or once every four weeks (i.e., 28-day cycle).Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0321] In some embodiments, the dosage amounts are administered every three weeks (i.e.21 day cycle),

[0322] In some embodiments, the dosage amounts are administered every four weeks (i.e.28 day cycle),

[0323] In some embodiments, the dosage amounts are administered every five weeks (i.e. 35 day cycle). In some embodiments, the dosage is administered on day 1 and on day 8 of every 4-week cycle (i.e., 28 day cycle).

[0324] In some embodiments, dosage amounts of the B7-H4-targeted antibody-drug conjugate are administered every one week (i.e. 7 day cycle), every two weeks (i.e. 14 day cycle), every three weeks (i.e. 21 day cycle), every four weeks (i.e. 28 day cycle), every five weeks (i.e. 35 day cycle), every six weeks (i.e. 42 day cycle), every seven weeks (i.e. 49 day cycle), or every eight weeks (i.e. 56 day cycle).

[0325] In some embodiments, a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) infusion is at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2and is administered as an infusion every one week (i.e. 7 day cycle), every two weeks (i.e. 14 day cycle), every three weeks (i.e. 21 day cycle), every four weeks (i.e. 28 day cycle), every five weeks (i.e. 35 day cycle), every six weeks (i.e. 42 day cycle), every seven weeks (i.e. 49 day cycle), or every eight weeks (i.e. 56 day cycle).

[0326] In some embodiments, a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) infusion is at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2and is administered as an infusion on day 1 and day 8 of each four week cycle (i.e. 28 day cycle).

[0327] In some embodiments, a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) infusion is at a dosage amount that is between about 28.7 mg / m2to about 115.0 mg / m2and is administered as an infusion on day 1 and day 8 of each four week cycle (i.e. 28 day cycle).

[0328] In some embodiments, a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) infusion is at a dosage amount that is between about 44.5 mg / m2to about 59.0 mg / m2and is administered as an infusion on day 1 and day 8 of each four week cycle (i.e. 28 day cycle).

[0329] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7,0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115,0 mg / m2, or between about 75.0 and about 115.0 mg / m2, once every 3 weeks (i.e, 21 day cycle). In some embodiments the subject is administeredAttorney Docket No.43704-02721 MRSN-047 / 001WO XMT-1660 at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37,0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, once every 4 weeks (i.e. 28 day cycle). In some embodiments the subject is administered XMT-1660 at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37,0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, once every 5 weeks (i.e. 35 day cycle). In some embodiments the subject is administered XMT-1660 at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, once every 6 weeks (i.e. 42 day cycle).

[0330] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, over 90 min for the first infusion, then over 90 minutes for the subsequent infusions once every 3 weeks (i.e. 21 day cycle).

[0331] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, over 90 min for the first infusion, then over 60 minutes for the subsequent infusions once every 3 weeks (i.e. 21 day cycle).

[0332] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, over 90 min for the first infusion, then over 30 minutes for the subsequent infusions once every 4 weeks (i.e. 28 day cycle).

[0333] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37.0 and about 115.0 mg / m2, or between about 75.0 and about 115.0 mg / m2, over 90 min for the first infusion, then over 30 minutes for the subsequent infusions once every 5 weeks (i.e. 35 day cycle).

[0334] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage amount that is between about 7.0 mg / m2to about 115.0 mg / m2, or between about 37,0 and about 115.0 mg / m2, or between about 75,0 and about 115.0Attorney Docket No. 43704-02721 MRSN-047 / 001WO mg / m2, over 90 min for the first infusion, then over 30 minutes for the subsequent infusions once every 6 weeks (i.e. 42 day cycle),

[0335] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 7.2 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks (i.e. 21 day cycle).

[0336] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 14.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0337] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 21.6 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0338] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 25.15 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0339] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 28.7 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0340] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 33.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0341] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 38.1 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0342] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 44.5 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0343] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 50.7 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0344] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 59.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks,

[0345] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 67.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0346] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 77.5 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0347] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 80.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0348] In some embodiments the subject is administered XMT-1660 at a dosage of about 87.6 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0349] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 95.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0350] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 115.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 3 weeks.

[0351] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 7.2 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every’ 4 weeks.

[0352] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 14.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0353] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 21.6 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0354] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 25.15 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0355] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 28.7 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0356] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 33.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0357] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 38.1 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0358] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 44.5 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0359] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 50.7 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0360] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 59.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0361] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 67.4 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0362] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 77.5 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0363] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 80.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0364] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 87.6 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks,

[0365] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 95.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0366] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 115.0 mg / m2over 90 min for the first infusion, then over 60 or 90 minutes for the subsequent infusions once every 4 weeks.

[0367] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 28.7 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0368] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 33.4 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0369] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 38.1 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0370] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 44.5 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0371] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 50.7 mg / m2on day 1 and on day 8 of a 4-weekAttorney Docket No.43704-02721 MRSN-047 / 001WO cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0372] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 59.0 mg / m2on day 1 and on day 8 of a 4- week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0373] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 67.4 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 mm for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0374] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 77.5 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0375] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 80.0 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0376] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of about 87.6 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0377] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 95.0 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g,, all infusions in cycles after cycle 1).Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0378] In some embodiments the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at a dosage of 115.0 mg / m2on day 1 and on day 8 of a 4-week cycle (i.e., 28-day cycle) over 90 min for the first two infusions (e.g., on day 1 and day 8 of cycle 1), then over 60 or 90 minutes for the subsequent infusions (e.g., all infusions in cycles after cycle 1).

[0379] The frequency and timing of administration, and the dosage amounts, can be administered periodically over a cycle of administration to maintain a continuous and / or long term effect of the active agents for a desired length of time. The provided compositions of a B7-H4-targeted antibody-drug conjugate can be administered hourly, daily, weekly, monthly, yearly or once. The length of time of the cycle of administration can be empirically determined, and is dependent on the disease to be treated, the severity of the disease, the particular patient, and other considerations within the level of skill of the treating physician. The length of time of treatment with a combination therapy provided herein can be one week, two weeks, one months, several months, one year, several years or more.

[0380] For example, the frequency of administration of the B7-H4-targeted antibody-drug conjugate is once a day, every other day, twice weekly, once weekly, once every 2 weeks, once every 3 weeks or once every 4 weeks. The dosage can be divided into a plurality of cycles of administration during the course of treatment. For example, the B7-H4-targeted antibody-drug conjugate can be administered at the frequency over a period of about a month, 2 months, 3 months, 4 months, 5 months, 6 months, a year or more. The frequency of administration can be the same throughout the period of the cycle or can differ. For example, an exemplary dosage frequency is two times a week at least for a first week of a cycle of administration. After the first week, the frequency can continue at twice a week, can increase to more than twice a week, or can be reduced to no more than once a week. It is within the level of a skilled person to determine the particular dosage frequency and cycle of administration based on the particular dosage being administered, the disease or condition being treated, the severity of the disease or condition, the age of the subject and other similar factors.

[0381] If disease symptoms persist in the absence of discontinued treatment, treatment can be continued for an additional length of time. Over the course of treatment, evidence of disease and / or treatment-related toxicity or side effects can be monitored.

[0382] The cycle of administration of the B7-H4-targeted antibody-drug conjugate can be tailored to add periods of discontinued treatment in order to provide a rest period from exposure toAttorney Docket No.43704-02721 MRSN-047 / 001WO the agents. The length of time for the discontinuation of treatment can be for a predetermined time or can be empirically determined depending on how the patient is responding or depending on observed side effects. For example, the treatment can be discontinued for one week, two weeks, three weeks, one month or several months. Generally, the period of discontinued treatment is built into a cycle of dosing regimen for a patient.

[0383] An exemplary dosing regimen is a treatment cycle or cycle of administration of 21 days or 28 days. Preferably, the dosing regimen is a treatment cycle or cycle of administration is 28 days. The B7-H4-targeted antibody-drug conjugate disclosed herein, is administered on day 1, followed by 20 days without dosing or is administered on day 1, followed by 27 days without dosing. It is within the level of one of skill in the art to determine the precise cycle of administration and dosing schedule.

[0384] In some embodiments, the administration is performed on day 1 of treatment, and every 3 weeks thereafter (e.g., on a three week cycle). In some embodiments, the administration is performed on day 1 of treatment, and every 4 weeks thereafter (e.g., on a four week cycle). In some embodiments, the administration is performed on day 1 of treatment, and every 5 weeks thereafter (e.g., on a five week cycle). In some embodiments, the administration is performed on day 1 of treatment, and every 6 weeks thereafter (e.g., on a six week cycle).

[0385] In some embodiments, the administration of the dose is performed on day 1 of each cycle.

[0386] In some embodiments, the administration of the dose is performed on day 1 of each cycle and administration of the dose is performed on day 8 of each cycle (e.g., each 4-week cycle).

[0387] In some embodiments, for a cycle of administration the dose is administered m more than one administration. For example, for one cycle, one- half dose is administered on day 1 of the cycle and one half-dose is administered on a subsequent day of the cycle such that the two half doses equal the total dose for the cycle. In an exemplary embodiment, the dose is administered for more than one cycle, wherein in each cycle, one-half of the dose is administered on day 1 of each cycle and one-half of the dose is administered on day 8 of each cycle, optionally wherein the cycle is a 3-week, 4-week, 5- week, or 6-week cycle.

[0388] In some embodiments, for a cycle of administration the dose is administered in more than one administration. For example, for one cycle, the full dose is administered on day 1 of the cycle and the full dose is administered on a subsequent day of the cycle such that the dose isAttorney Docket No. 43704-02721 MRSN-047 / 001WO administered twice per cycle. In an exemplary embodiment, the dose is administered for more than one cycle, wherein in each cycle, the dose is administered on day 1 of each cycle and the dose is administered on day 8 of each cycle, optionally wherein the cycle is a 3 -week, 4-week, 5- week, or 6-week cycle, e.g. a 4-week cycle,

[0389] As noted above, the cycle of administration can be for any desired length of time. Hence, the 21 -day cycle or 28-day cycle of administration can be repeated for any length of time. For example, the 21 -day cycle or 28-day cycle of administration can be repeated for 2 months, 3, months, 4 months, 5, months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1.5 years, 2 years, 2.5 years, 3 years or more. It is within the level of skill of the treating physician to adopt a cycle of administration and dosing regimen that meets the needs of the patient depending on personal considerations specific to the patient and disease to be treated.

[0390] In some embodiments, the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) until disease progression, death, unacceptable toxicity or voluntary withdrawal - whichever comes first.

[0391] The disclosure provides a B7-H4-targeted antibody drug conjugate for use in combination with an ACE inhibitor and / or an ARB for the treatment of cancer in a subject; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):Attorney Docket No.43704-02721 MRSN-047 / 001WO / o ANTIBODY / iiwherein i. dis is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRE1 ) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc;is Fuc; and > is GalNAc.

[0392] The disclosure provides a B7-H4-targeted antibody drug conjugate for use in combination with a SGLT2 inhibitor for the treatment of cancer in a subject; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):Attorney Docket No.43704-02721 MRSN-047 / 001WO / o ANTIBODY / iiwherein i. dis is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRE1 ) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc;is Fuc; and > is GalNAc.

[0393] The disclosure provides an ACE inhibitor and / or an ARB, for use in combination with a B7-H4-targeted antibody-drug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated withAttorney Docket No.43704-02721 MRSN-047 / 001WO a B7-H4-targeted antibody-drug conjugate; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I),wherein i. di3 is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), in. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; is Fuc; and > is GalNAc.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0394] The disclosure provides an SGLT2 inhibitor, for use in combination with a B7-H4-targeted antibody-drug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated with a B7-H4-targeted antibody-drug conjugate; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I),wherein i, di3 is about 2; ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GHVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7), hi. the Drug is attached to a heavy chainAttorney Docket No. 43704-02721 MRSN-047 / 001WO of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and iv. ■ is GlcNAc; A is Fuc; and > is GalNAc.Dose reductions and delays

[0395] In some cases, toxicity or adverse reactions may occur in response to the initial dose of a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) at the doses described herein.Subsequent doses may be reduced or time between doses may be delayed or extended. In some embodiments, toxicity or adverse reactions that may result in a dose reduction or delay include, but are not limited to, increased ALT or AST levels, interstitial lung disease (ILD), pneumonitis, corneal AEs, increased creatinine levels, proteinuria, thrombocytopenia, hypertension, increased troponin I levels, other clinically significant non-laboratory toxicities, other clinically significant adverse events. In embodiments, the subject is monitored for one or more of: (a) liver enzyme (e.g., AST and / or ALT) levels; (b) blood platelet count; (c) blood pressure; (d) creatinine, (e) proteinuria, and if the subject exhibits any one of the following, for example, within 7 days prior to a scheduled administration of the B7-H7-targeted antibody drug conjugate,:(i) Grade 2 or higher AST and / or ALT elevation (e.g., AST and / or ALT levels are greater than 3 times the levels prior to first treatment);(ii) Proteinuria of +2 or higher on 2 consecutive dipstick tests or +3 or higher on one dipstick test (or, optionally, urinary’ protein greater than or equal to 3.5 g / 24hhours);(iii) systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg which remains unresolved for more than 5 days;(vi) platelet count less than 75x109 / L; and / or(v) serum creatine levels greater than 1.5 times the levels prior to first treatmentthe subject is administered a lower dose at the next dosing, optionally wherein said lower dose is one dose level (e.g,, as defined on Table 1) lower than was previously administered.Combination Therapies

[0396] In some embodiments, the subject is administered a B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) m combination with one or more additional therapeutic agents. In some embodiments, the antibody drug conjugate is administered in combination with an immune checkpoint inhibitor molecule. In some embodiments, the immune checkpoint inhibitor molecule is a PD-1 -binding molecule, e.g., an anti-PD-1 antibody, or a PD-Ll-binding molecule, e.g., an antiAttorney Docket No.43704-02721 MRSN-047 / 001WO PD-L1 antibody. In some embodiments, the antibody drug conjugate and the immune checkpoint inhibitor molecule are administered concurrently or sequentially.

[0397] In some embodiments, a conjugate disclosed herein, or a pharmaceutical composition thereof, is administered to a subject as provided above, and further in combination with an additional therapeutic agent, e g., a PD-1 antagonist; a PD-L1 antagonist; a topoisomerase inhibitor or an ADC thereof (i.e., a TOPO-1 inhibitor ADC), such as, for example sacituzumab govitecan, TRODELVY or ENHERTU, or a TOPO-1 inhibitor ADC targeting B7-FI4 such as, for example, AZD8025, HS-20089, GSK5733584, or a topoisomerase 1 inhibitor-containing antibody drug conjugate described in WO2022 / 068878); a chemotherapeutic agent (e.g. a platinum-based chemotherapeutic agent), such as, for example, docetaxel, doxorubicin, cyclophosphamide, carboplatin, paclitaxel, nab-paclitaxel, gemcitabine, and cisplatin; an antineoplastic agent such as, for example, atezolizumab; an angiogenesis inhibitors, such as, for example, bevacizumab (Avastin); an AKT inhibitor, such as, for example, ipatasertib; a PARP inhibitor, such as, for example, olaparib (Lynparza), rucaparib (Rubraca), talazoparib, and niraparib (Zejula); a cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor, such as, for example, palbociclib, ribociclib and abemaciclib; a selective estrogen receptor antagonist, such as, for example, fulvestrant (Faslodex); a mTOR inhibitor, such, as, for example, everolimus (Afinitor); a PI3K inhibitor such as, for example, alpelisib; an additional ADC; or a combination thereof.

[0398] In some embodiments, the additional therapeutic agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), MEDI-0680 (AMP-514; WO2012 / 145493). camrelizumab (SHR-1210), tislelizumab (BGB-A317), or spartalizumab (NPVPDR001, NVS240118, PDR001). The additional therapeutic agent may also include pidilizumab (CT- 011). A recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224, can also be used to antagonize the PD-1 receptor.

[0399] In some embodiments, the PD-L1 antagonist, is an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, atezolizumab (TECENTRIQ), durvalumab (MEDI4736), BMS-936559 (W02007 / 005874), avelumab (WO2013 / 79174) or rHigM12B7.

[0400] In some embodiments, e.g., when the cancer is a Her2 cancer, an additional therapeutic agent is trastuzumab. Trastuzumab emtansine (Kadcyla®) pertuzumab (Perjeta®), tyrosine kinase inhibitors, such as, for example, lapatinib and tucatinib.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0401] Such combination therapies noted above encompass combined administration (where two or more therapeutic agents are included in the same or separate formulations), and separate administration, m which case, administration of the antibody or antibody-drug conjugate of the invention can occur prior to, simultaneously, and / or following, administration of the additional therapeutic agent and / or adjuvant. B7-H4-targeted antibody-drug conjugates of the invention can also be used in combination with radiation therapy.Manufacture of a Medicament

[0402] The present disclosure provides use of a conjugate disclosed herein in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. In some embodiments, the present disclosure provides use of a B7-H4-targeted antibody-drug conjugate in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof. In some embodiments, the present disclosure provides use of a B7-H4-targeted antibody-drug conjugate in the manufacture of a medicament for treating? XCC, triple negative breast cancer (TNBC), hormone receptor positive / HER2 negative (HR+ / HER2-) breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, in a subject in need thereof.

[0403] Before, during, or following administration of a B7-H4-targeted antibody-drug conjugate of the disclosure the subject may be monitored for the presence, level, or quantity of one or more clinical biomarker, biological molecule, or clinical trait. In some embodiments, a subject’s liver enzyme (e.g., AS T and / or ALT) levels may be monitored. In some embodiments, a subject’s blood platelet count may be monitored. In some embodiments, a subject’s blood pressure may be monitored. In some embodiments, a subject’s proteinuria levels may be monitored. In some embodiments, a subject’s creatinine levels may be monitored. In some embodiments, a subject’s troponin I levels may be monitored. In some embodiments, if the subject exhibits any one of the following within 7 days prior to a scheduled administration of the B7-H7 -targeted antibody drug conjugate:(i) Grade 2 or higher AST and / or ALT elevation (e.g., AST and / or ALT levels are greater than 3 times the levels prior to first treatment);(ii) Proteinuria of +2 or higher on 2 consecutive dipstick tests or +3 or higher on one dipstick test (or, optionally, urinary protein greater than or equal to 3.5 g / 24 hours);Attorney Docket No.43704-02721 MRSN-047 / 001WO (iii) systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg which remains unresolved for more than 5 days;(vi) platelet count less than 75x109 / L; and / or(v) serum creatine levels greater than 1.5 times the levels prior to first treatment;the subject is administered a lower dose at the next dosing, optionally wherein said lower dose is one dose level (e.g,, as defined on Table 1 ) lower than was previously administered.Kits

[0404] The disclosure provides kits comprising a B7-H4-targeted antibody-drug conjugate of the disclosure. In some embodiments, the disclosure provides a kit comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an ACE inhibitor and / or an ARB. In some embodiments, the disclosure provides a kit comprising: (a) a B 7- H4- targeted antibody-drug conjugate and (b) an SGLT2 inhibitor. In some embodiments, the disclosure provides a kit comprising: (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor. In some embodiments, kits of the disclosure optionally include instructions of use.Pharmaceutical Compositions

[0405] The disclosure provides pharmaceutical compositions comprising a B7-H4-targeted antibody-drug conjugate of the disclosure. In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) a B7-H4-targeted antibody-drug conjugate and (a) an ACE inhibitor and / or an ARB, for use in combination. In some embodiments, the disclosure provides pharmaceutical compositions comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an ACE inhibitor and / or an ARB, for use in combination. In some embodiments, the disclosure provides pharmaceutical compositions comprising (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor for use in combination.Measurement of B7-H4 Expression

[0406] In various embodiments the invention provides a method for identifying a cancer patient amenable to B7-H- targeted therapy or monitoring the treatment regimen by measuring the status of B7-H4 expression in a tumor sample obtained from the patient.

[0407] In some embodiments, the B7-H4 diagnostic tests can be used to identify subjects for treatment with the B7-H4-targeted drug conjugate.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0408] The sample is derived from the subject having a cancer. The sample of cancer cells is dissected from tissue removed or obtained from the subject. In some embodiments, the sample is a fresh, frozen or an archival biopsy sample,

[0409] In some embodiments, the test cell population is derived from fresh, unfrozen tissue from a biopsy sample. In other embodiments, the test cell population is derived from a primary or metastatic site. In some embodiments, the test cell population is derived from a fresh or frozen tissue from a biopsy or surgical sample or ascitic fluid or pleural fluid. In some embodiments, the test cell population is derived from a fixed tissue (e.g., formalin fixation or formalin-fixed paraffin- embedded (FFPE)) from a biopsy or surgical sample or cell block derived from a fluid specimen. The tissue sample may be frozen or fresh.

[0410] The requisite level of B7-H4 expression may be that which is identified by the any methods known in the art and more specifically by the methods described herein. For example, the level of B7-H4 expression can be measured by conducting a known immunological assay, such as an enzyme immunoassay, radioimmunoassay, competitive immunoassay, double antibody sandwich assay, fluoroimmuno assay, ELISA, Western blotting technique, agglutination assay, cytofluorometry (e.g. flow cytometry), Fluorescence in situ hybridization (FISH), colorimetric or immunohistochemical staining assay (IHC) for protein expression using an antibody that specifically recognizes B7-H4. Cell-based assays, such as, for example, flow cytometry (FC), immuno-histochemistry (IHC), RNA expression analysis or immunofluorescence (IF ) are particularly desirable in determining B7-H4 expression status, since such assay formats are clinically-suitable.

[0411] Flow cytometry' (FC) may be employed to determine cell surface expression of B7-H4 in a tumor sample before, during, and after treatment with a drug. For example, tumor cells may be analyzed by flow cytometry for B7-H4 expression, as well as for markers identifying cancer cell types, etc., if so desired. Flow cytometry’ may be carried out according to standard methods. See, e.g. Chow et al., Cytometry (Communications m Clinical Cytometry) 46: 72-78 (2001). Briefly and by way of example, the following protocol for cytometric analysis may be employed: fixation of the cells with 2% paraformaldehyde for 10 minutes at 37 °C. followed by permeabilization in 90% methanol for 30 minutes on ice. Cells may then be stained with B7-H4-specific antibody, washed and labeled with a fluorescent-labeled secondary antibody. The cells would then be analyzed on aAttorney Docket No. 43704-02721 MRSN-047 / 001WO flow cytometer (e.g. a Beckman Coulter FC500) according to the specific protocols of the instrument used. Such an analysis would identify the level of expressed B7-H4 in the tumor.

[0412] Immunohistochemical (IHC) staining may be also employed to determine the expression of B7-H4 in a tumor sample before, during, and after treatment with a drug. IHC may be carried out according to well-known techniques. See, e g., ANTIBODIES; A LABORATORY MANUAL, Chapter 10, Harlow & Lane Eds., Cold Spring Harbor Laboratory (1988). Briefly, and by way of example, paraffin- embedded tissue (e.g. tumor tissue from a biopsy) is prepared for immunohistochemical staining by deparaffinizing tissue sections with xylene followed by ethanol; hydrating in water then PBS; unmasking antigen by heating slide in sodium citrate buffer; incubating sections in hydrogen peroxide; blocking in blocking solution; incubating slide in primary polypeptide antibody and secondary antibody; and finally detecting using ABC avidin / biotin method according to manufacturer's instructions.

[0413] Immunofluorescence (IF) assays may be also employed to determine the expression of B7-H4 tumor sample before, during, and after treatment with a drug. IF may be earned out according to well-known techniques. See, e.g., J. M. Polak and S. Van Noorden (1997) INTRODUCTION TO IMMUNOCYTOCHEMISTRY, 2nd Ed.; ROYAL MICROSCOPY SOCIETY MICROSCOPY HANDBOOK 37, BioScientific / Springer- Verlag. Briefly, and by way of example, patient samples may be fixed in paraformaldehyde followed by methanol, blocked with a blocking solution such as horse serum, incubated with the primary antibody against polypeptide followed by a secondary antibody labeled with a fluorescent dye such as Alexa 488 and analyzed with an epifluorescent microscope.

[0414] Antibodies employed in the above-described assays may be advantageously conjugated to fluorescent dyes (e.g. Alexa488, PE), or other labels, such as quantum dots, for use in multi-parametric analyses along with other signal transduction (phospho- AKT, phospho-Erk 1 / 2) and / or cell marker (cytokeratin) antibodies.

[0415] In one embodiment the expression of B7-H4 in a sample from a tumor is determined immunohistochemically, using a system, for example, a Leica Bond III Fully automated Stainer (BOND III) system.

[0416] Alternatively, the assay may include preparing RNA from the sample, optionally for use in PCR (polymerase chain reaction) or other analytical methodology. The PCR methodology is optionally, for example, RT-PCR (reverse transcription-PCR) or quantitative PCR, such as, forAttorney Docket No.43704-02721 MRSN-047 / 001WO example, real-time RT-PCR, RNA seq and the like. Alternatively, the assaying may be conducted by use of an array, such as a microarray as known in the relevant field, such as, for example, nanostring technologies.

[0417] Patients are identified as being responsive to treatment, wherein the treatment is monitored or cancer is detected by detecting and / or measuring the expression level of B7-H4 in the tumor cells in a sample.

[0418] The detection / measurement of the expression level of B7-H4 is determined by¬ calculating a B7-H4 score. The B7-H4 score is quantitative or semi quantitative. For example, detection is scored pathologically to arrive at a pathology score. It is contemplated that any scoring methods known in the art may be used in the methods of the invention. In particular, any histological scoring methods known in the art.

[0419] The detection / measurement of the expression level of B7-H4 is determined by calculating a B7-H4 score. In embodiments, the B7-H4 score is quantitative or semi quantitative. For example, detection is scored pathologically to arrive at a pathology score. It is contemplated that any scoring methods known in the art is used in the methods of the present disclosure. In particular, any histological scoring method known in the art is used. In embodiments, the histological method is performed on a tumor biopsy by B7-H4 immunohistochemistry (IHC). IHC is carried out, for example, using a B7-H4 binding molecule, for example, recombinant anti-B7-H4 antibody EPR20236 (Abeam). In embodiments, the B7-H4 binding molecule binds to a different epitope of B7-H4 than XMT-1660 (e.g., is not competitive or is only weakly competitive for binding to B7-H4 with XMT-1660 by a BIACORE or similar binding assay). Immunohistochemical results for B7-H4 expression are expressed at a staining intensity score where 0 is unstained; I is weak staining; 2 is moderate staining; and 3 is strong staining.

[0420] The methods for assessing the measurement results obtained by immunohistochemical staining assays include, for example, the H-score method, TPS (tumor proportion score) or PS2+ (percent score) score. The H-score (Am. J Clin. Pathol. 1988; 90 (3): 233-9, the contents of which are incorporated herein by reference in their entirety), TPS score and PS2+ scores are determined by the following calculation formula: H-Score = ((% tumor cells, e.g., viable tumor cells, with staining intensity score 0) x 0) + ((% tumor cells, e.g., viable tumor cells, with staining intensity score 1+) x 1) + (( % tumor cells, e.g,, viable tumor cells, with staining intensity score 2+) x 2) + ((% tumor cells, e.g., viable tumor cells, with staining intensity score 3+)Attorney Docket No. 43704-02721 MRSN-047 / 001WO x 3); TPS-score = (% tumor cells, e.g., viable tumor cells, with staining intensity score at 1+) + ( % tumor cells, e.g., viable tumor cells, with staining intensity score at 2+) + (% tumor cells, e.g., viable tumor cells, with staining intensity score at 3+); and PS2+ score = ( % tumor cells, e.g., viable tumor cells, with staining intensity score at 2+) + (% tumor cells, e.g., viable tumor cells, with staining intensity score at 3+). In some embodiments the subject is considered B7-H4 positive with a B7-H4 score, e.g., a B7-H4 TPS score, more than low (e.g., moderate or high). In some embodiments, the subject is considered B7-H4 positive with a B7-H4 TPS of greater than or equal to 50%. In other embodiments, the subject is considered B7-H4 positive with a B7-H4 TPS of greater than or equal to 70%.

[0421] In assessment by the scoring method, only cancer cells, e.g., viable cancer cells, are considered for the analysis. For negative or positive controls for staining intensity, formalin-fixed paraffin-embedded cell lines or xenografts (lines whose protein expression levels are known in advance) may be employed. When there are no control specimens, a plurality of specimens are assessed simultaneously to confirm the overall distribution of staining intensity of the specimens, and then staining intensity may be set.

[0422] In addition to the scoring methods mentioned above, other scoring methods known in the art, such as, for example, the Allred method (Harvey, et al. Journal of Clinical Oncology 17, No.5 (May 1999) 1474-1474), can also be used. Allred score = score of percentage of positive cells + staining intensity score. Cut-off points are required to be set in each method.

[0423] In some embodiments, the subject with ACC is identified for treatment by (a) identification of an activating mutation a Notch pathway gene (e.g., NOTCH-1, NOTCH-2, NOTCH-3, or NOTCH-4), optionally in the NOTCH-1 gene, optionally as identified by next¬ generation sequencing (NGS); and / or (b) a tumor biopsy testing positive for c-MYC and negative or low-expressing for TP63, optionally as measured by immunohistochemistry (IHC).

[0424] In some embodiments, the subject with ACC is identified for treatment by having a clinical course characterized by <3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with atypical sites of metastases (e.g. bone, CNS, and non-pulmonary or -hepatic viscera) and a solid tumor morphology on histologic evaluation. 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 B7-H4-targeted antibody-drug conjugates disclosed herein by identifying the B7-H4 score of the subject prior to treatment with a B7-H4-targetedAttorney Docket No. 43704-02721 MRSN-047 / 001WO antibody-drug conjugate disclosed herein. In some embodiments, the test cell population is derived from fresh, unfrozen ti sue 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 B7-H4 receptor protein on the surface of cells in a cancer tissue sampleDEFINITIONS

[0425] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0426] As used herein, the terms "anti-B7-H4 antibody", “B7-H4 antibody” and "an antibody that binds to B7-H4" refer to an antibody that is capable of binding B7-H4 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting B7-H4

[0427] The term " B7-H4," as used herein, refers to any native, mature B7-H4 which results from processing of a B7-H4 precursor protein in a cell. The term includes B7-H4 from any vertebrate source, including mammals such as primates (e.g. humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. The term also includes naturally occurring variants of B7-H4, e.g., splice variants or allelic variants.

[0428] The term " B7-H4-positive cancer" refers to a cancer comprising cells that express B7-H4 on their surface. In some embodiments, expression of B7-H4 on the cell surface is determined, for example, using antibodies to B7-H4 in a method such as immunohistochemistry, FACS, etc. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 50%. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 50%. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 55%. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 60%. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 65%. In some embodiments, a B7-H4-positive cancer has been identified as such based on a B7-H4 TPS of greater than or equal to 70%.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0429] Alternatively, B7-H4 mRNA expression is considered to correlate to B7-H4 expression on the cell surface and can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

[0430] The term " B7-H4-positive cell" refers to a cell that expresses B7-H4 on its surface.

[0431] The term "antibody" as used herein, is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. Various methods are known in the art for numbering the amino acids sequences of antibodies and identification of the complementary determining regions. For example, the Rabat numbering system (See Rabat, E. A., et al., Sequences of Protein of immunological interest, Fifth Edition, US Department of Health and Human Services, US Government Printing Office (1991)) or the IMGT numbering system (See IMGT'*; the international ImMunoGeneTics information system^. Available online, http: / / www.imgt.org / ). The IMGT numbering system is routinely used and accepted as a reliable and accurate system in the art to determine amino acid positions in coding sequences, alignment of alleles, and to easily compare sequences in immunoglobulin (1G) and T-cell receptor (TR) from all vertebrate species. The accuracy and the consistency of the IMGT data are based on IMGT-ONTOLOGY, the first, and so far unique, ontology for immunogenetics and immunoinformatics (See Lefranc. M. P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139). IMGT tools and databases run against IMGT reference directories built from a large repository of sequences. In the IMGT system the IG V-DOMAIN and IG C-DOMAIN are delimited taking into account the exon delimitation, whenever appropriate. Therefore, the availability of more sequences to the IMGT database, the IMGT exon numbering system can be and “is used” by those skilled in the art reliably to determine amino acid positions in coding sequences and for alignment of alleles. Additionally, correspondences between the IMGT unique numbering with other numberings (i.e., Rabat) are available in the IMGT Scientific chart (See Lefranc. M. P. et al., Biomolecules, 2014 Dec; 4(4), 1102-1139). The EU numbering system (See Edelman, G. M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) can also be used. In some aspects, EU numbering can be used to number amino acid positions of an antibody In some aspects, the EU numbering system can be used to determine position of the constant region of an antibody heavy chain or light chain.

[0432] The term "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an inta ct antibody and that binds the antigen to which the intact antibody binds.Attorney Docket No.43704-02721 MRSN-047 / 001WO Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.

[0433] The term "antibody that binds to the same epitope" as a reference antibody as used herein, refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay is provided herein.

[0434] The term "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG2, IgG3, IgGi, IgAi, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, E, y, and p, respectively.

[0435] The term "monoclonal antibody" as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., comprising naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals comprising all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0436] The term a "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety or STING agonist drug moiety). The naked antibody may be present in a pharmaceutical formulation.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0437] The term "native antibodies" refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from - to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain.

[0438] An "isolated antibody" is one which has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary¬ electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0439] The term "epitope" refers to the particular site on an antigen molecule to which an antibody binds.

[0440] The term “humanized antibody” of an antibody refers to an antibody that is derived from a non-human antibody (e.g., murine) that retains or substantially retains the antigen-binding properties of the parent antibody but is less immunogenic in humans. Humanized as used herein is intended to include deimmunized antibodies.

[0441] The term "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0442] The term “competes with” or “cross-competes with” when used herein in the context of two or more antibodies, indicates that the two or more antibodies compete for binding to B7-H4, e.g., compete for B7-H4 binding. An antibody “blocks” or “cross-blocks” one or more other antibodies from binding to B7-H4 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing “partial block” and 75%-400% representing “full block”. Unless otherwise defined or negated by context, the terms “competes with”, “cross-competes with”, “blocks” or “cross-blocks” when used herein is also intended to cover such pairs of antibodies.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0443] As used herein, an antibody that "specifically binds to human B7-H4" is intended to refer to an antibody that binds to human B7-H4 with a KD of 1 x 10'7or less, more typically 5 x 10'8M or less, more typically 3 x 10'8M or less, more typically 1 x IO'9M or less, even more typically 5 x 10'9M or less.

[0444] The term "does not substantially bind" to a protein or cells, as used herein, means does not bind or does not bind with a high affinity to the protein or cells, i.e. binds to the protein or cells with a KD of 1 x 10'8M or more, more preferably 1 x 10"5M or more, more preferably 1 x IO"4M or more, more preferably 1 x 10'3M or more, even more preferably 1 x 10'2M or more.

[0445] The term “sugar" refers to a monosaccharide, for example glucose (Glc), galactose (Gal), mannose (Man) and fucose (Fuc). The term "sugar derivative" refers to a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and / or functional groups. Examples of a sugar derivative include, but are not limited to, amino sugars and sugar acids. Examples of a sugar derivative also include compounds denoted as S’(F’)xi, wherein S’ is a sugar or a sugar derivative, F” is a functional group and xi indicates the number of functional groups.

[0446] The term “core-GlcNAc moiety”, as used herein, refers to a monosaccharide, polysaccharide, or oligosaccharide moiety comprising a GlcNAc (e.g., a core-GlcNAc) which is attached to an antibody (e.g., via the Cl position of the GlcNAc). In some embodiments, the GlcNAc is attached to the antibody via an N-glycosidic bond to the amide nitrogen atom in the side chain of an asparagine amino acid of the antibody. In some embodiments, the core-GlcNAc moiety is present at a native glycosylation site of an antibody or is introduced on a different site on the antibody. In some embodiments, the core-GlcNAc moiety is a monosaccharide (e.g., the core-GlcNAc moiety' is also a temiinal-GlcNAc moiety). In some embodiments, the core-GlcNAc moiety further comprises a fucose, e.g., the core-GlcNAc moiety is a disaccharide core-GlcNAc-(al-6-Fuc) moiety (which may be referred to as GlcNAc(Fuc)). Thus, when antibody comprises a core-GlcNAc moiety, the antibody may comprise a monosaccharide or a disaccharide core-GlcNAc moiety', and the core-GlcNAc moiety may further comprise a fucose (e.g., a disaccharide core-GlcNAc(Fuc) moiety). If the core-GlcNAc moiety further comprises a fucose, the fucose may be linked a- 1,6 to O-6 of the core-GlcNAc moiety. A core-GlcNAc moiety further comprising a fucose may be referred to as core-GlcNAc(Fuc).

[0447] The term “core-GlcNAc” refers to the inner GlcNAc that is a portion of a polysaccharide or oligosaccharide, wherein the polysaccharide or oligosaccharide is attached to an antibody via the inner GlcNAc.Attorney Docket No. 43704-02721 MRSN-047 / 001WO

[0448] The term “terminal-GlcNAc moiety”, as used herein, refers to a moiety comprising a GlcNAc which is attached to an antibody and has a terminal functional group being available for further modification (e.g., with a compound of P”-S”-A”). In some embodiments, the terminal-GlcNAc moiety further comprises a fucose. In some embodiments, the terminal-GlcNAc moiety is formed by reacting the core-GlcNAc moiety of a glycoprotein (e.g,, an antibody glycan) with an endoglycosidase.

[0449] The term "nucleotide" is used in its normal scientific meaning and refers to a molecule that is composed of a nucleobase, a five-carbon sugar (either ribose or 2-deoxyribose), and one, two or three phosphate groups. Without the phosphate group, the nucleobase and sugar compose a nucleoside. A nucleotide can thus also be referred to as a nucleoside monophosphate, a nucleoside diphosphate or a nucleoside triphosphate. The nucleobase may be adenine, guanine, cytosine, uracil or thymine.

[0450] The term "protein" is used in its normal scientific meaning and includes polypeptides comprising about 10 or more amino acids. A protein may comprise natural or unnatural amino acids.

[0451] The term "glycoprotein" is herein used in its normal scientific meaning and refers to a protein comprising one or more monosaccharide or oligosaccharide chains ("glycans") covalently bonded to the protein. A glycan may be attached to a hydroxyl group on the protein (O-linked-glycan), to an amide function on the protein (N-gly coprotein), or to a carbon on the protein (C-glycoprotein). A glycoprotein may comprise more than one glycan, may comprise a combination of one or more monosaccharide and one or more oligosaccharide glycans, and may comprise a combination of N-linked, O-linked and C-linked glycans. It is estimated that more than 50% of ail proteins have some form of glycosylation and therefore qualify as glycoprotein.

[0452] The term "glycan" is herein used in its normal scientific meaning and refers to a monosaccharide or oligosaccharide chain that is linked to a protein. Glycan thus refers to the carbohydrate-part of a glycoprotein. The glycan is attached to a protein via the C-l carbon of one sugar, which may be without further substitution (monosaccharide) or may be further substituted at one or more of its hydroxyl groups (oligosaccharide). A naturally occurring glycan typically comprises 1 to about 10 saccharide moieties, However, when a longer saccharide chain is linked to a protein, said saccharide chain is also considered a glycan. A glycan of a glycoprotein may be a monosaccharide, A glycan may also be an oligosaccharide. An oligosaccharide chain of a glycoprotein may be linear or branched. In an oligosaccharide, the sugar that is directly attached toAttorney Docket No. 43704-02721 MRSN-047 / 001WO the protein is called the core sugar. In an oligosaccharide, a sugar that is not directly attached to the protein and is attached to at least two other sugars is called an internal sugar. In an oligosaccharide, a sugar that is not directly attached to the protein but to a single other sugar, i.e. carrying no further sugar substituents at one or more of its other hydroxyl groups, is called the terminal sugar. For the avoidance of doubt, there may exist multiple terminal sugars in an oligosaccharide of a glycoprotein, but only one core sugar. A glycan may be an O-linked glycan, an N-linked glycan, or a C-linked glycan. In a delinked glycan, a monosaccharide or oligosaccharide glycan is bonded to a C-atom in an amino acid of the protein.

[0453] The term “glycosyltransferase” refers to a superfamily of enzymes that are involved in the synthesis of complex carbohydrates present on glycoproteins and glycolipids.

[0454] The term “N-acetylgalactosaminyl transferase” (GalNAc-T) is a N-acetyl-D-galactosamine transferase enzyme that catalyzes the addition of N-acetyl-D-galactosamine to proteins.

[0455] The term "independently", as used herein, means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0456] The term "pharmaceutically acceptable", as used herein, refers to those compounds, conjugates, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0457] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0458] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0459] A therapeutically "effective amount" is intended to mean that amount of a conjugate that, when administered to a patient in need of such treatment, is suffi cient to effective treat or prevent,Attorney Docket No. 43704-02721 MRSN-047 / 001WO as defined herein. The amount of a given conjugate that will correspond to such an amount will vary depending upon factors such as the particular conjugate (e.g., the potency (pICso), efficacy (ECso), and the biological half-life of the particular conjugate), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before / with / after meals) of the conjugate will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular conjugate and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art. In embodiments, a therapeutically effective amount of a B7-H4 antibody-drug conjugate (e.g., as described herein, e.g., emiltatug ledadotin) includes the doses and dose regimens described herein.

[0460] The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.

[0461] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0462] The terms "conjugate(s) of the disclosure" or "conjugate(s) of the present disclosure", as used herein, mean a conjugate as defined herein, in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.

[0463] Accordingly, included within the present disclosure are the conjugates as disclosed herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the conjugates of the present disclosure, in any salt or non-salt form, and in any physical form thereof, may have varyingAttorney Docket No.43704-02721 MRSN-047 / 001WO levels of activity, different bioavailabilities and different handling properties for formulation purposes.

[0464] It is understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0465] When used herein in the context of two or more antibodies, the term “competes with” or “cross-competes with” indicates that the two or more antibodies compete for binding to B7-H4, e.g., compete for B7-H4 binding in the assay described in Examples 5 or 8. An antibody “blocks” or “cross-blocks” one or more other antibodies from binding to B7-H4 if the antibody competes with the one or more other antibodies 25% or more, with 25%-74% representing “partial block” and 75%-400% representing “full block”, preferably as determined using the assay of Examples 5 and 8. For some pairs of antibodies, competition or blocking in the assay of the Examples 5 or 8 is only observed when one antibody is coated on the plate and the other is used to compete, and not vice versa. Unless otherwise defined or negated by context, the terms “competes with”, “cross-competes with”, “blocks” or “cross-blocks” when used herein is also intended to cover such pairs of antibodies.

[0466] As used herein, "dosing regimen" or “dosage regimen” refers to the amount of agent, for example, the composition comprising an B7-H4-targeted antibody-drug conjugate, administered, and the frequency of administration. The dosing regimen is a function of the disease or condition to be treated, and thus can vary.

[0467] As used herein, "frequency" of administration refers to the time between successive administrations of treatment. For example, frequency can be days, weeks or months. For example, frequency can be more than once weekly, for example, twice a week, three times a week, four times a week, five times a week, six times a week or daily. Frequency also can be one, two, three or four weeks. The particular frequency is a function of the particular disease or condition treated.Generally, frequency is more than once weekly, and generally is twice weekly.

[0468] As used herein, a "cycle of administration" refers to the repeated schedule of the dosing regimen of administration of the enzyme and / or a second agent that is repeated overAttorney Docket No.43704-02721 MRSN-047 / 001WO successive administrations. For example, an exemplary cycle of administration is a 28-day cycle with administration once, on day 1 of the cycle. In another example, an exemplary cycle of administration is a 28-day cycle wherein the dose is administered in more than one part, for example part (e.g., half) of the dose is administered on one day of the cycle (e.g., day 1) and part (e.g., half) of the dose is administered on a different day of the cycle (e.g., day 8). In another example, an exemplary cycle of administration is a 28-day cycle wherein the dose is administered on Day 1 and Day 8 of the 28-day cycle dosing.

[0469] As used herein, when referencing dosage based on mg / kg of the subject, an average human subject is considered to have a mass of about 70 kg-75 kg, such as 70 kg and a body surface area (BSA) of 1.73 m2.

[0470] As used herein, amelioration of the symptoms of a particular disease or disorder by a treatment, such as by administration of a pharmaceutical composition or other therapeutic, refers to any lessening, whether permanent or temporary, lasting or transient, of the symptoms or, adverse effects of a condition, such as, for example, reduction of adverse effects associated with or that occur upon administration of an B7-H4-targeted antibody-drug conjugate.

[0471] As used herein, when referencing dosage based on “body surface area” (BSA; m2) is the measured or calculated surface area of a human body. For many clinical purposes BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass. Various calculations have been published to arrive at the BSA without direct measurement. In the following formulae, BSA is in m2, W is mass in kg, and H is height in cm. The most widely used is the Du Bois, Du Bois formula: BSA= 0.007184 x W0.425x H0.723. Other methods of determining BSA include for example, the Mosteller, Haycock, Gehan and George, Boyd, Fujimoto, Takahira, Shuter and Aslani or Schlich formulas.

[0472] A “subject” includes a mammal. The mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or a pig.Preferably, the mammal is a human.

[0473] As used herein, “unit dose form” or “unit dosage form” refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art,

[0474] As used herein, a single dosage formulation refers to a formulation as a single dose.

[0475] As used herein, “temporal proximity” refers to that administration of one therapeutic agent (e.g., a B7-H4-targeted antibody-drug conjugate disclosed herein) occurs within a time periodAttorney Docket No.43704-02721 MRSN-047 / 001WO before or after the administration of another therapeutic agent (e.g., an immune checkpoint inhibitor disclosed herein), such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeuti c effect of the one therapeutic agent completely overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen.

[0476] As used herein a “kit” refers to a combination of components, such as a combination of the compositions herein and another item for a purpose including, but not limited to, reconstitution, activation and instruments / devices for delivery, administration, diagnosis and assessment of a biological activity or property. Kits optionally include instructions of use.

[0477] As used herein “prior line of a platinum-containing regimen” include:i. Adjuvant ± neoadjuvant considered as one line of therapy as long as they are the same regimens (e.g., platinum / taxane for 4 cycles before surgery followed by platinum / taxane for 4 cycles after surgery7)Attorney Docket No. 43704-02721 MRSN-047 / 001WO ii. Maintenance therapy (e.g., bevacizumab, PARPi or endocrine therapy) will be considered part of the preceding line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines.iii. Therapy given for only 1 cycle and discontinued due to toxicity in the absence of progression will not be counted as a line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines.iv. Hormonal therapy (e.g., tamoxifen, letrozole) will be counted as a separate line of therapy unless it was given as maintenance.

[0478] As used herein “recurrent disease” refers to a subject having disease progression following partial or complete response to one or more therapeutics. In some embodiments, the recurrence can be local to the original site of disease (i.e. one or more ovaries) or at a distal or metastatic location.

[0479] The present disclosure is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0480] The present disclosure is intended to include all isomers of the compound, which refers to and includes, optical isomers, and tautomeric isomers, where optical isomers include enantiomers and diastereomers, chiral isomers and non-chiral isomers, and the optical isomers include isolated optical isomers as well as mixtures of optical isomers including racemic and non-racemic mixtures; where an isomer may be in isolated form or in a mixture with one or more other isomers.

[0481] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.OTHER EMBODIMENTS

[0482] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to beAttorney Docket No. 43704-02721 MRSN-047 / 001WO incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.EXAMPLES

[0483] The following examples are illustrative and are not intended to be limiting and it will be readily understood by one of skill in the art that other reagents or methods may be utilized.ABBREVIATIONS

[0484] The following abbreviations are used in the reaction schemes and synthetic examples, which follow. This list is not meant to be an all-inclusive list of abbreviations used in the application as additional standard abbreviations, which are readily understood by those skilled in the art of organic synthesis, can also be used in the synthetic schemes and examples.Abbreviation Full TermACC Adenoid Cystic CarcinomaACC-1 Adenoid Cystic Carcinoma Type IACE angiotensin converting enzymeADA Anti-drug antibodyADC Antibody-drug conjugateAE Adverse eventAF Auristatin FAF-HPA Auristatin F hydroxypropyl amide or XMT-1267ALT Alanine transaminase or alanine aminotransferaseARB angiotensin II receptor blockerAST Aspartate transaminase or aspartate aminotransferaseAUC Area under the curveAUCo-last Area under the concentration curve for the last measurable concentration BSA Body surface areaCmax Concentration at maximum levelAttorney Docket No.43704-02721 MRSN-047 / 001WO Abbreviation Full TermCR Complete responseCTCAE Common Toxicity Criteria for Adverse EventsDAR Drug to antibody ratioDCR Disease control rateDES Dose escalationDL Dose levelDLT Dose-limiting toxicityDOR Duration of responseEFREAS Efficacy Response Evaluable Analysis SetECG Electrocar di ogramECHO EchocardiogramEGFR Epidermal growth factor receptorER Estrogen receptorEXP ExpansionHER2 Human epidermal growth factor receptor 2HR+ Hormone receptor positiveIHC immunohistochemistryINR International normalized ratioIRR Infusion- related reactionHBV Hepatitis B virusHCV Hepatitis C virusHIV Human immunodeficiency virusmAb Monoclonal antibodyMTD Maximum tolerated doseMUGA Multi gated acquisition scannAb Neutralizing antibodyNCI National Cancer InstituteNSAID Non-steroidal anti-inflammatory drugORR Objective response rateOS Overall survivalAttorney Docket No. 43704-02721 MRSN-047 / 001WO Abbreviation Full TermPD-LI Programmed death ligand- 1PFS Progression-free survivalPK PharmacokineticsPR Partial responsePT Prothrombin timeq3w Every 3 weeks dosingQ4W Every 4 weeksRP2D Recommended Phase 2 doseRECIST Response Evaluation Criteria in Solid TumorsSAE Serious adverse eventSAP Statistical analysis planSGLT2 sodium -glucose co transporter-2SRC Safety Review Committeet½ Terminal eliminationtmax Time of maximum observed concentrationTNBC Triple negative breast cancerTPS tumor proportion scoreuACR urine albumin to creatinine ratioULN Upper limit of normalVEGF vascular endothelial growth factorVss Volume of distributionWOCBP Woman of childbearing potentialXMT-1604 B7-H4 antibodyXMT-1660 B7-H4 antibody-drug conjugateGENERAL INFORMATION

[0485] The B7-H4-targeted antibody-drug conjugate (e.g. XMT-1660) was prepared as described in US Patent Application No. 17 / 568,376.The complementarity determining regions (CDR) are defined in accordance to the IMGT numbering system (See IMGT®, the international ImMunoGeneTics information system®. Available online: http: / / www. imgt. org / ).Attorney Docket No. 43704-02721 MRSN-047 / 001WO Example 1: Clinical Study Design and Methodology

[0486] The FIH study of XMT-1660 is a Phase 1, open-label study of XMT-1660 in previously treated participants with the following advanced / metastatic cancers: triple negative breast cancer (TNBC); hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HER2-) BC; endometrial cancer (EC); ovarian cancer (OC) (including fallopian tube and primary peritoneal cancer); and adenoid cystic carcinoma Type I (ACC-I).

[0487] The study is composed of Dose Escalation (DES), Backfill Cohorts, and Expansion (EXP). DES will be the dose-finding segment of the study to assess the safety and tolerability of XMT-1660 and determine the maximum tolerated dose (MTD), and data from DES and the Backfill Cohorts will be used to determine a dose(s) considered for the recommended Phase 2 dose (RP2D). EXP will evaluate the safety and preliminary efficacy of XMT-1660 in specific tumor types at a dose(s) or regimen considered for the RP2D.

[0488] The Bayesian optimal interval (BOIN) design will be used to determine the MTD in DES, with the target dose-limiting toxicity (DLT) rate set at 30%. There are 12 dose levels described herein in Table 1, but it is possible that intermediate or higher dose levels or alternative dose regimens could be added based on emerging data. It is also possible that not all planned dose levels will be evaluated.

[0489] Initial dose escalation will be conducted per the scheme below. A single-participant cohort will be used for the first dose level (Dose Level [DL] 1) and for DL1.5 if it is opened. All cohorts for subsequent dose levels will have at least 3 participants.

[0490] Cycles will be defined as either 21 days, 28 days, or 42 days to facilitate either a q3w, q4w, or q6w dosing schedule. If a Day 1 and Day 8 of a 28-day cycle (2 times every 4 weeks [2q4w]) dosing schedule is used, a cycle will be defined as 28 days.

[0491] A single-participant cohort will be utilized for the first dose level (Dose Level (DL) 1). All cohorts for subsequent dose levels will have at least 3 participants.Table 1 - Dosing Levels for qXw or 2Q4W (dld8) DosingAttorney Docket No.43704-02721 MRSN-047 / 001WODL XMT-1660 Dose qXw regimen XMT-1660 Dose2q4w Day 1 and Day 8 of 28-day Cycle dosing schedule1 7.2 mg / m2—2 14.4 mg / m2""3 21.6 mg / m2—4e28.7 mg / m228.7 mg / m2on Day 1 and again on Day 8(maximum total dose of 59.0 mg per (maximum total dose of 59.0 mg per administration) administration)5e38.1 mg / m238.1 mg / m2on Day 1 and again on Day 8(maximum total dose of 76.0 mg per (maximum total dose of 76.0 mg per administration) administration)5.5d’s44.5 mg / m244.5 mg / m2on Day 1 and again on Day 8(maximum total dose of 90.0 mg per (maximum total dose of 90.0 mg per administration) administration)6s50.7 mg / m250.7 mg / m2on Day 1 and again on Day 8 (maximum total dose of 100.0 mg per (maximum total dose of 100.0 mg per administration) administration)6.5d, e59.0 mg / m259.0 mg / m2on Day 1 and again on Day 8 (maximum total dose of 118.0 mg per (maximum total dose of 118.0 mg per administration) administration)7e67.4 mg / m267.4 mg / m2on Day 1 and again on Day 8 (maximum total dose of 135.0 nig per (maximum total dose of 135.0 mg per administration) administration)8s80.0 mg / m280.0 mg / m2on Day 1 and again on Day 8 (maximum total dose of 160.0 mg per (maximum total dose of 160.0 mg per administration) administration)9e95.0 mg / m295.0 mg / m2on Day 1 and again on Day 8 (maximum total dose of 190.0 mg per (maximum total dose of 190.0 mg per administration) administration)10e115.0 mg / m2115.0 mg / m2on Day 1 and again on Day 8 (maximum total dose of 230.0 mg per (maximum total dose of 230.0 mg peradministration) administration) Abbreviations: 2q4w=2 times every 4 weeks; AE=adverse event; BSA=body surface area;DES=Dose Escalation; DL=Dose Level; DLT=dose-limiting toxicity; qXw=every X weeks;SRC=Safety Review Committee.d- DL5.5 and DL6.5 are considered full dose levels for the purposes of dose modification guidance.e- XMT-1660 doses at DL4 and above will be capped based on a maximum total dose corresponding to approximately a BSA of 2.0 m2.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0492] In addition, any dose of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) for Dose Levels 4.0 and above will be capped based on a maximum total dose corresponding to approximately a BSA of 2.0 m2.

[0493] Initially, the B7-H4-targeted antibody-drug conjugate (e.g,, XMT-1660) will be dosed every 3 weeks (q3w; on a 3-week cycle) or every 4 weeks (q4w; on a 4-week cycle); however, alternative cycle lengths are contemplated herein, e.g., as described herein. When the Day 1 and Day 8 of a 28-day cycle (2 times every 4 weeks (2q4w (dld8))) dosing schedule is implemented, participants are expected to receive the full amount of the Dose Level (starting with Dose Level 4, 28.7 mg / m2 on Day 1 and again on Day 8 of every cycle). It is possible that different doses may be delivered on Day 1 and Day 8 of the 28-day cycle dosing schedule based on emerging data. Treatment will continue indefinitely until disease progression, an unacceptable adverse event, pregnancy, participant noncompliance with the protocol as outlined in the informed consent form, the participant withdraws, general or specific changes in the participant’s condition render the participant unacceptable for further treatment, the sponsor decides to terminate the study, or loss of follow-up. In certain instances, the patent may continue on treatment past progression with approval from the study medical monitor.

[0494] In parallel with DES, optional Backfill Cohorts will enroll additional participants into tumor type- specific cohorts at a selected dose level(s) from DES that is lower than the dose level currently enrolling participants in DES. The Backfill Cohorts may include participants with TNBC; HR+, HER2- BC; and EC; or OC (including fallopian tube and primary peritoneal cancer). Up to 12 participants per tumor type at a specific dose level and / or schedule may be added.

[0495] Backfill Cohorts may be initiated at multiple dose levels simultaneously; these dose levels will be selected based on the totality of available safety, efficacy, PK, and pharmacodynamic (PD) data emerging from DES. The totality of the data from DES and the Backfill Cohorts will be evaluated for determination of a dose(s) considered for the RP2D. It is possible that Backfill Cohorts for some tumor types and dosing regimens will only enroll participants in a B7-H4 tumor proportion score (TPS) high (e.g., >50%) subgroup.

[0496] EXI’ will employ a Simon 2-stage design to evaluate both the safety and preliminary efficacy of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at the MTD and / or a dose(s) considered for the RP2D. The dose and schedule will be based on cumulative data from DES and Backfill cohorts. To further support optimal dose selection, EXP may have multiple dose level or dosing schedule cohorts for each dosing regimen evaluated. The study will enrollAttorney Docket No.43704-02721 MRSN-047 / 001WO participants with advanced / metastatic conditions of: (1) TNBC; (2) HR+, HER2- BC; (3) EC; (4) OC (including fallopian tube and primary peritoneal cancer); and (5) ACC-I. The EXP cohort will include subjects with TNBC that had 1 to 4 prior lines of treatment, including at least one topoisomerase 1 inhibitor antibody-drug conjugate, and whose TNBC status has been determined by ASCO / CAP guidelines. This cohort will include subjects who were HR: at the time of their breast cancer diagnosis and subjects having their HER2- status indicated by a HER2 immunohistochemistry (IHC) result of 0 or 1 or an IHC result of 2 combined with a negative fluorescence in-situ hybridization (FISH) result. The EXP cohort has been initiated for patients with TNBC who have received 1 -4 prior lines of therapy in the metastatic setting, including at least one topoisomerase- 1 inhibitor-containing ADC. The EXP dose regimen involves treatment with XMT-1660 at a dose of 67.4 mg / m2administered on day 1 of treatment and every 4 weeks thereafter (e.g., Q4W). Tumors from patients treated with either EXP dose regimen are assessed for B7-H4 expression and are grouped as B7-H4-high or B7-H4-low as described herein.

[0497] During EXI’, participants are required to provide a tumor tissue sample, either archived or from a fresh biopsy prior to enrollment (during a Prescreening Period). Participants will not be subject to a significant risk biopsy procedure for the purpose of obtaining tissue sample for participating in the EXI’ portion of the study. This sample will undergo prospective B7-H4 expression analysis by a centralized lab. The purpose of B7-H4 expression analysis is to classify participants into TPS subgroups based on their results: High, Medium, or Low, or TPS Low vs. TPS High. A tumor will be scored TPS Low if the TPS score is <50% and TPS High if >50% or >70%. In EXP, the Simon 2-stage design will be employed for each tumor type cohort for each dosing regimen evaluated to assess the initial activity of XMT-1660 dosing regimens for each TPS subgroup, except for the ACC-I cohort, which will be considered an all-comers cohort. Each tumor type TPS Low cohort will proceed to Stage 2 if >1 response is observed in Stage 1. Each tumor type TPS High cohort and the ACC-I cohort will proceed to Stage 2 if >2 responses are observed in Stage 1. A response will be defined as a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, EXP cohorts for some tumor types and dosing regimens will only enroll participants in the TPS High (>50%) subgroup.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0498] Based on emerging safety, efficacy, PK, and / or PD data, additional doses and / or schedules of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) might be investigated, e.g., as described herein, within each tumor type,

[0499] It is possible that some of the mentioned tumor types might not undergo evaluation during EXP, or that new tumor types could be investigated based on emerging data. If new tumor types are considered for the study, the design will be revised accordingly.

[0500] In all parts of the study (DES, Backfill, and EXP), blood sampling will be performed to determine the levels of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660’s) components, including total antibody (e.g., XMT-1604), conjugated and free payload (e.g., auristatin F hydroxypropyl amide (AF-HPA)), and the primary metabolite of XMT-1267 (e.g., Auristatin F (AF)). PK parameters will then be determined from these analytes. Testing for anti-drug antibodies (ADAs) and neutralizing antibodies (nAbs) will be performed. Testing for PD markers will also be conducted.Study ObjectivesPrimary Objectives:

[0501] The primary objectives for each stage of the study are described below:Dose Escalation• Determine the MTD of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) • Assess the safety and tolerability of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660)Backfill Cohorts» Assess the safety and tolerability of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at selected doses being considered for the RP2DExpansion• Assess the safety and tolerability of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at a dose(s) considered for the RP2D• Assess the preliminary anti-tumor activity of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at a dose(s) considered for the RP2D

[0502] The secondary and exploratory objectives for each stage of the study are described below:Attorney Docket No.43704-02721 MRSN-047 / 001WO Secondary Objectives'.• DES only: assess the preliminary anti-tumor activity of the B7-H4-targeted antibodydrug conjugate (e.g., XMT-1660)• Backfill Cohorts only: assess the preliminary anti-tumor activity of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at selected doses being considered for the RP2D• EXP only: further assess the preliminary anti-tumor activity of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) at a dose(s) considered for the RP2D • Assess the PK of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660), its release products, and selected metabolites• Assess the development of AD As and nAbs to the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660)Exploratory Objectives:• Evaluate the tumor expression of B7-H4 and programmed death ligand- 1 (PD-L1) by immunohistochemistry, as applicable by tumor type• Assess the association of the level of B7-H4 expression with the anti-tumor activity of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660)® Evaluate expression of other markers related to cancer or inflammation in relation to clinical outcome® Evaluate population PK and any exposure / response relationships of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660), as appropriate• Evaluate the effect of ADA on PK, safety, and efficacy, as appropriateStudy Eligibility:

[0503] To be eligible for the study, all participants must fulfil all the inclusion criteria and none of the exclusion criteria, as defined below:General Inclusion Criteria

[0504] Participants will be eligible for the study if all of the following criteria are met:Attorney Docket No.43704-02721 MRSN-047 / 001WO Participant has a proven recurrent or advanced solid tumor and has disease progression after treatment with available anti-cancer therapies known to confer benefit or is intolerant to treatment,Participant must be at least 18 years of age.Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.Participant must have cardiac left ventricular ejection fraction >50% or > the institution’s lower limit of normal (LLN) by either echocardiogram (ECG), multigated acquisition scan (MUGA), or an alternative modality that is considered more accurate.Participants with toxicity from prior therapy or surgical procedures must have recovered to Grade <1. Participants with alopecia. Grade 2 peripheral sensory neuropathy, stable immune-related toxicity such as hypothyroidism on hormone replacement therapy, or adrenal insufficiency treated with <10 mg daily prednisone (or equivalent) are an exception to this criterion and may qualify for this study.Participant must have adequate organ function within 14 days prior to Cycle 1 Day 1 and again on Cycle 1 Day 1 (±3 days) as defined by the following criteria:Absolute neutrophil count >1500 cells / mm³(ANC), not induced by Myeloid growth factors cannot be used within 7 days granulocyte (short-acting growth factors) or 21 days (long-acting colony-stimulating factors growth factors) of CID 1 laboratory testing.Platelet count >100,000 / mm3Prophylactic transfusion of blood (or blood components) within 14 days prior to Screening cannot be used to meet enrollment criteria.Platelet growth factor agents cannot have been used within 14 days prior to or during screening.Attorney Docket No.43704-02721 MRSN-047 / 001WO Absolute neutrophil count >1500 cells / mm3(ANC), not induced by Myeloid growth factors cannot be used within 7 days granulocyte (short-acting growth factors) or 21 days (long-acting colony-stimulating factors growth factors) of C1D1 laboratory testing.Hemoglobin >9 g / dLProphylactic transfusion of blood (or blood components) or an erythropoietin-stimulating agent within 14 days prior to Screening cannot be used to meet enrollment criteria.PT < Institutional upper limit of normal (ULN)International normalized <1.2xULNratio (INR) orActivated partial <1.2xULNthromboplastin time Exception: Participants with falsely elevated aPTT not (aPTT) associated with risk of increased bleeding may be allowed Estimated glomerular >60 mL / min according to the (Chronic Kidney Disease filtration rate (eGFR) Epidemiology Collaboration) CKD-EPI Creatinine EquationUrine protein by urinalysis Negative or trace. If >1+, must be <500 mg protein in 24- hour urine collection.dipstick valueTotal bilirubin <1.2xULNDirect bilirubin < ULNNote: Participants with asymptomatic elevations in direct bilirubin due to Gilbert syndrome or stable chronic hemolytic anemia (e.g. hereditary spherocytosis, sickle cell disease, and thalassemia intermedia) may be eligible.Attorney Docket No.43704-02721 MRSN-047 / 001WO Absolute neutrophil count >1500 cells / mm3(ANC), not induced by Myeloid growth factors cannot be used within 7 days granulocyte (short-acting growth factors) or 21 days (long-acting colony-stimulating factors growth factors) of C1D1 laboratory testing.Aspartate <1.5xULNaminotransferase (AST or orserum <2.0 - ULN (if known liver metastases)glutamic-oxaloacetictransaminase (SGOT)) andalanine aminotransferase(ALT or serumglutamic-pyruvictransaminase (SGPT)).Albumin >3.0 g / dL.During the study, women of childbearing potential (WOCBP) must use a contraceptive method that is highly effective (with a failure rate of <1% per year when used correctly and consistently) during study treatment and for 6 months after the last dose of the B7-H4- targeted antibody-drug conjugate (e.g., XMT-1660).Male study participants must use barrier contraception (condoms) and refrain from donating sperm for the duration of study treatment and for at least 6 months after the last dose of study treatment. Partners of male study participants considered to be WOCBP must use a highly effective contraceptive method for the same duration.. Participant must have at least 1 measurable lesion(s), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.. Participant must be willing to undergo a minimally invasive tumor biopsy to obtain tumor tissue for local testing, if medically feasible, prior to Cycle 1 Day 1. In addition, an archival tissue sample, if available, should be submitted to a central laboratory to enable a longitudinal analysis of tumor biomarkers.Attorney Docket No. 43704-02721 MRSN-047 / 001WO 12. Participants must undergo MRI brain imaging during the Screening period unless obtained within 30 days prior to enrollment (Pre-Screening Period; based on standard clinical care) to confirm eligibility if they meet either of the following criteria:a. All participants with TNBCb. Participant has a history of brain metastases; or neurologic symptoms or signs suspicious for brain metastases.The result of the MRI brain imaging, if required, must not demonstrate any evidence of brain hemorrhage, including micro-hemorrhage.General Exclusion Criteria

[0505] Participants will not be eligible for study entry if any of the following criteria are met:1. Participant has received prior treatment with another ADC containing an auristatin payload.2. Participant has received prior B7 H4--targeted treatment.3. Participant has a history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy.4. Participant has received a vascular endothelial growth factor (VEGF)-targeted therapy.5. Participant has had major surgery within 28 days of starting study treatment; systemic anti-cancer therapy within the time period of 28 days or 5 half-lives of the prior therapy- before starting study treatment (14 days or 5 half-lives for small molecule targeted therapy), whichever is less; or palliative radiation therapy to the chest within 3 months of starting study treatment or to other anatomic sites within 14 days of starting study treatment.6. Participant has a diagnosis of an additional malignancy that required active treatment (including surgery, systemic therapy, and radiation) within 2 years prior to Screening, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the breast or of the cervix. Participants with an additional malignancy that has a low risk for recurrence may be eligible.7. Participant has untreated hepatitis B virus (HBV) or hepatitis C virus (HCV).• HBV: Participants with HBV infection must have hepatitis B surface antigen (HbsAg) (-) and hepatitis B core antibody (HbcAb) (+) serology and have an HBV viral loadAttorney Docket No.43704-02721 MRSN-047 / 001WO (as determined by polymerase chain reaction [PCR]) below the limit of quantification to be eligible.• HCV: Participants with a history of HCV infection should have completed curative anti-viral treatment and have an HCV viral load (as determined by PCR) below the limit of quantification to be eligible.Participant has an HIV infection.Participant has a history of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver diseases. Liver function testing beyond laboratory assessments otherwise defined in the eligibility criteria to diagnose potentially clinically significant liver disease based on risk factors such as hepatic steatosis or history of excessive alcohol intake will be based on clinical judgment of the Investigator.Participant may not receive a drug associated with hepatotoxicity concurrent with the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) administration. Participants may receive acetaminophen / paracetamol for a limited time but at a total daily dose of <2 g per day. Use of non-steroidal anti-inflammatory drugs or steroids for treatment of fever is encouraged.Participant has active bleeding or pathologic conditions that carries high risk of bleeding such as known bleeding disorder, coagulopathy, or tumor involving major vessels per Investigator judgement.Participant has current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary’, or metabolic disease) or intercurrent illness that could increase the risk of serious adverse events or interfere with per-protocol evaluations.Participants with the following characteristics are excluded:• a marked baseline prolongation of QT / corrected QT (QTc) interval of Common Terminology Criteria for Adverse Events (CTCAE) Grade >1: repeated demonstration of a QT interval corrected using Fndericia’s formula (QTcF) interval>480 milliseconds on more than one electrocardiogram;• a history of additional risk factors for Torsades de Pointes (e.g. family history of long QT syndrome);Participant has clinically significant cardiovascular disease, including:Attorney Docket No.43704-02721 MRSN-047 / 001WO • Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg.• Myocardial infarction or unstable angina within 6 months prior to first dose of study treatment.• New York Heart Association (N YHA) Grade II or greater congestive heart failure • CTCAE Grade 2 or greater peripheral vascular disease (at least brief (<24 hrs) episodes of ischemia managed non-surgically and without permanent deficit) within 6 months prior to first dose of study treatment.• History of CVA within 6 months prior to first dose of study treatment.Participant is receiving concurrent anti-cancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy, immunotherapy, hormone therapy, and investigational therapy).Participant is unable or unlikely to comply with the dosing schedule and study evaluations. Participant has history’ of or suspected pneumonitis or interstitial lung disease.Participant currently uses either constant or intermittent supplementary oxygen therapy. Participant has oxygen saturation on room air of <93%.Participant is using strong cytochrome P4503 A inhibitors or inducers that cannot be discontinued while receiving study treatment. Participants currently on these medications must be discontinued within 14 days of the first dose of study treatment.Participant has untreated central nervous system (CNS) metastases (including new and progressive brain metastases), a history of leptomeningeal metastasis, or carcinomatous meningitis.a. Participants are eligible if CNS metastases are adequately treated, and participants are neurologically stable for at least 2 weeks prior to enrollment. b. In addition, participants must be either off corticosteroids or on a stable / decreasing dose of <10 mg daily prednisone (or equivalent).Anticonvulsants are allowed, except for those drugs associated with hepatotoxicity.c. Participants may be eligible if CNS lesions are asymptomatic, equivocal for metastases or do not require specific therapy.Attorney Docket No. 43704-02721 MRSN-047 / 001WO 22. Participant is a pregnant or nursing woman. In WOCBP, pregnancy status must be confirmed with a negative, highly sensitive pregnancy test before study entry and while receiving study treatment,23, Participant has received a live / attenuated vaccine within 30 days before study entry (first dose) or plans to receive a live / attenuated vaccine while on study treatment through 90 days after the last dose of study treatment.24, Participant has known sensitivity to the study treatment(s) or any components thereof, including diluent.Disease-Specific Eligibility Criteria:

[0506] TNBC-specific Inclusion Criteria include:1. Participants with a histologically or cytologically proven diagnosis of BC with evidence of locally advanced or metastatic disease for whom experimental therapy is appropriate.2. Participant has documentation of estrogen receptor-negative (ER-), progesterone receptor-negative (PR-), HER2- BC based on local testing of their most recent tumor biopsy as defined in the relevant American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines.3. Participant has received prior therapy as follows:a. DES and Backfill Cohorts: Participant has received at least 2 lines of systemic therapy in a locally advanced or metastatic BC setting.b. EXP: Participant has received 1 to 4 prior lines of systemic therapy in a locally advanced or metastatic BC setting, 1 of which must have included an approved ADC. Treatment in the neoadjuvant or adjuvant setting is not counted toward the prior lines of therapy. For participants with a breast cancer gene (BRCA) mutation, prior treatment with a poly (ADP-ribose) polymerase inhibitor (PARPi) is allowed and will not be counted toward prior lines of chemotherapy.

[0507] TNBC-specific Exclusion Criteria: None

[0508] HR+, HER2- BC-specific Inclusion Criteria include:1. Participants with a histologically or cytologically proven diagnosis of BC with evidence of advanced or metastatic disease for whom experimental therapy is appropriate.Attorney Docket No. 43704-02721 MRSN-047 / 001WO 2. Participant has documentation of estrogen receptor-positive (ER+) and / or progesterone receptor-positive (PR+), HER2- BC based on local testing of their most recent tumor biopsy as defined in the relevant ASCO / CAP guidelines.3. Participant has received prior therapy as follows:a. DES and Backfill Cohorts: Participant has received at least 1 line of systemic therapy in an advanced or metastatic BC setting. Participants with tumor expression of both progesterone receptor (PR) and estrogen receptor (ER) >= 10% by immunohistochemistry are required to have received a cyclin-dependent kinase (CDK)4 / 6 inhibitor(s) (e.g. abemaciclib, palbociclib, and ribociclib) and endocrine therapy (ET) in an advanced or metastatic BC setting.b. EXP:- Participant has received at least 1 line of systemic therapy in an advanced or metastatic BC setting. Participants whose tumor expression of both progesterone receptor (PR) and estrogen receptor (ER) is >10% by immunohistochemistry are required to have received prior therapy with a CDK4 / 6 inhibitor(s) (e.g. abemaciclib, palbociclib, and ribociclib) combined with ET in any setting.- Participant has not received more than 3 prior lines of chemotherapy (including ADCs) for advanced or metastatic disease. For participants with aBRCA mutation, prior treatment with a PARPi is allowed and will not be counted toward prior lines of chemotherapy.

[0509] HR+, HER2- BC-specific Exclusion Criteria include: None

[0510] EC-specific Inclusion Criteria include:1. Participants with a histologically or cytologically proven diagnosis of endometrial carcinoma with evidence of locally advanced or metastatic disease who have no satisfactory treatment options and for whom experimental therapy is appropriate.2. Participant has received prior therapy as follows:a. DES and Backfill Cohorts: Participant has received at least 1 line of systemic therapy. b. EXP: Participant has received at least 1 prior line of platinum -doublet chemotherapy and no more than 3 prior lines of systemic therapy for recurrent or metastatic disease, not including hormone therapy. Participants with microsatellite instability (MSI) highAttorney Docket No.43704-02721 MRSN-047 / 001WO tumors are required to receive at least one line of therapy containing a PD-1 or a PD-L1 inhibitor.

[0511] EC-specific Exclusion Criteria include:1. Participant has a diagnosis of sarcoma arising from the uterus,2. Participant has a diagnosis of carcinosarcoma.

[0512] OC-specific Inclusion Criteria include:1. Participants with a histologically proven diagnosis of OC, including fallopian tube and primary peritoneal cancer, that is recurrent or metastatic,2. EXP: Participant must have platinum-resistant recurrent disease, defined as completing >3 cycles of platinum-based therapy and radiographically progressing within 6 months of the last platinum-based therapy.• Participants who have received 1 prior line of chemotherapy must have achieved a complete response (CR) or partial response (PR) to that therapy and experienced disease progression between 3 to 6 months after the last dose of platinum- based therapy in the first-line setting.• Participants who have received 2 to 4 prior lines of chemotherapy must have experienced disease progression within <6 months after the last dose of platinum-based therapy in their most recent line of chemotherapy.3. Participant has received prior therapy as follows:a. DES and Backfill Cohorts: Participant has received at least 2 lines of systemic therapy, one of which must have included platinum-based chemotherapy for advanced or metastatic disease. Participants who were not eligible to receive platinum-based therapy may be eligible.b. EXP: Participant must have received 1 to 4 prior lines of systemic therapy for OC including at least 1 prior line of a platinum-containing regimen.• Criteria for prior lines of therapy are as follows:Adjuvant and neoadjuvant therapy are considered 1 line of therapy as long as they are the same regimen (e.g. platinum / taxane for 4 cycles before surgery followed by platinum / taxane for 4 cycles after surgery).Attorney Docket No. 43704-02721 MRSN-047 / 001WO - Maintenance therapy (e.g. bevacizumab, PARPi, ET) will be considered part of the preceding line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines.- Therapy given for only 1 cycle and discontinued because of toxicity in the absence of disease progression will not be counted as a line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines.- Hormone therapy (e.g. tamoxifen, letrozole) will be counted as a separate line of therapy unless it was given as maintenance therapy.

[0513] OC-specific Exclusion Criteria include:1. Participant has a low-grade, mucinous, carcinosarcoma, germ-cell, or stromal tumor.2. EXP: Participant has primary platinum-resistant disease, defined by a lack of response or disease progression within 3 months after completing front-line, platinum-containing therapy. It is possible that the EXP cohort could be limited based on tumor histology.

[0514] ACC-I specific Inclusion Criteria include:1. Participants with histologically proven diagnosis of ACC with evidence of locally advanced, recurrent or metastatic disease for whom experimental therapy is appropriate.2. ACC Type I (ACC-I) disease demonstrated by one or both of the following:» Any in-house or commercial next generation sequencing (NGS) assay showing an activating mutation in NOTCH1 or other Notch pathway genes (NOTCH1-4), or a positive expression for c-MYC per immunohistochemistry or negative / low-expression for TP63 (p63) per immunohistochemistry.• Clinical course characterized by < 3 years from diagnosis to initialrecurrence / progression or de novo metastatic disease with atypical sites of metastases (i.e., bone, CNS, visceral non-pulmonary / non-hepatic) and solid tumor morphology on histologic evaluation.

[0515] ACC-I Specific Exclusion Criteria: None.Criteria for EvaluationSafety

[0516] Frequency and grade of adverse events and serious adverse events based on National Cancer Institute CTCAE version 5.0.Attorney Docket No.43704-02721 MRSN-047 / 001WO

[0517] Changes in clinical laboratory parameters (hematology, chemistry, urinalysis), vital signs, ECOG performance status, electrocardiogram parameters, physical examinations, and use of concomitant medications.Clinical Activity

[0518] Tumor response assessed by the Investigator per RECIST version 1.1

[0519] Objective response rate (ORR), defined as the percentage of participants who achieve a best overall response of confirmed CR or PR,

[0520] Duration of response (DOR), defined as the time from when response criteria are first met until disease progression or death in participants who achieve confirmed CR or PR.

[0521] Disease control rate (DCR), defined as the percentage of participants who achieve CR, PR, or stable disease as the result of study treatmentPharmacokinetics and Immunogenicity

[0522] PK parameters of the B7-II4-targeted antibody-drug conjugate (e.g., XMT-1660), its release products, and selected metabolites.

[0523] Plasma samples for analysis of the B7-II4-targeted antibody-drug conjugate (e.g., XMT-1660) ADA and nAb levels.

[0524] PK profile of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660), its release products, and selected metabolites.

[0525] Covariate effect evaluation on relevant parameters of the population PK and exposure / response models.

[0526] Effect of ADA on PK, safety, and efficacy.Pharmacodynamics and Biomarkers

[0527] Correlative measures for ORR, DOR, and DCR with alternative assays for measurement of B7 H4 expression, PD LI expression (as applicable), expression of other genes or proteins, and expression of other markers related to cancer or inflammation.Dose-limiting Toxicities

[0528] Frequency of DLTs associated with the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) during the first cycle of treatment in DES.

[0529] DLT Observation Period: The DLT Observation Period is the time between the initiation of the Cycle 1 infusion of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660)Attorney Docket No.43704-02721 MRSN-047 / 001WO and completion of Cycle 1 (e.g. 21 days for q3w dosing or 28 days for q4w dosing) and should include the pre dose assessments before receiving the Cycle 2 dose.

[0530] A DLT is defined as any toxicity not due to disease progression or another clearly identifiable cause detailed in the protocol that occurs within the DLT Observation Period.Rationale for the Study.

[0531] Despite advances in therapies conferring benefits in progression-free survival and overall survival, the majority of patients with advanced / metastatic BC, EC, OC, and ACC-I either do not respond or eventually acquire resistance to these therapies and die from their disease.Therefore, advanced / metastatic BC, including TNBC and HR+, HER2- BC along with EC, OC, and ACC-I remain serious and life-threatening conditions with an unmet medical need.

[0532] Notably, B7-H4 protein expression has been observed in various human tumors such as BC, EC, OC, and ACC-I. In addition, B7-H4 expression in tumor cells of some of these malignancies appears to be associated with disease progression and poor prognosis. For example, B7-H4 is expressed in approximately 77% of TNBC tumors and approximately 60% of HR+ and HER2+ tumors. B7-H4 expression was high in approximately 45% of BCs and was independent of estrogen receptor and HER2 status. Further, B7-H4 was reported as broadly expressed in ECs and OCs. B7-H4 has been cited as being over-expressed in 85% of ACC-I tumors, which is prognostic of worse overall survival.

[0533] The hypothesis is that by targeting B7-H4, the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) will confer clinical benefit to patients with advanced / metastatic TNBC, HR+, HER2- BC, EC, OC, and ACC-I who have exhausted available standard therapy options for treatment of their disease. To test this hypothesis, the FIH study with XMT-1660, a B7-H4-directed ADC with a cytotoxic auristatin payload, will be initiated in tumors likely to express B7-H4.

[0534] Adenoid cystic carcinoma type I (ACC-I) is a rare secretory gland malignancy most commonly arising from the salivary glands with approximately 2,300 new cases diagnosed in the United States annually. Recently, two distinct molecular subtypes have been identified - ACC-I, representing approximately 37% of cases, characterized by enrichment of NOTCH1-activating mutations, upregulation of MYC, and upregulation of MYC target genes and exhibiting an aggressive clinical behavior; and ACC-II, representing approximately 63% of cases, characterized by upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR), and exhibiting an indolent course. The estimated median survival for ACC-I is approximately 3.4 years, and there areAttorney Docket No.43704-02721 MRSN-047 / 001WO currently no approved systemic therapies for patients who fail surgery’ and radiation therapy for localized tumors or who have metastatic disease. B7-H4 is overexpressed in 85% of ACC-I tumors and is an independent predictor of poor overall survival.

[0535] Although there are no universal standards for classification of ACC as ACC-I, the diagnosis has been characterized by expert sources using a combination of molecular, histopathologic and clinical features. These include activating mutations in NOTCH 1 or other Notch pathway genes (NOTCH1-4), the combination of immunohistochemistry (IHC) positive for c-MYC and negative / low-expression for TP63, predominantly solid tumor morphology (rather than cribriform, tubular) on histologic evaluation, and clinical course characterized by a relatively short period of time from diagnosis to initial recurrence / progression or de novo metastatic disease with atypical sites of metastases (i.e., bone, CNS, visceral non-pulmonary / non-hepatic).Dosing and Administration of XMT-1660

[0536] The B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) is administered according to body surface area (BSA). The Mosteller Formula will be used for calculation of BSA. The starting dose will be calculated based on height and weight collected within 14 days of the first dose (can be collected the day of first dose). Dose calculations in subsequent cycles should be made for weight changes >5% from the most recent dose calculation.

[0537] The B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) is intravenously via an antecubital or in-dwelling venous catheter. Administration procedures will ensure that the entire scheduled dose is delivered and that no part of the scheduled dose remains in the infusion line.

[0538] The initial dose for each participant will be administered over 90 minutes. If no IRR occurs, all subsequent doses can be administered over 60 (±10) minutes, e.g., may be administered over a period of 60-90 minutes. During Cycle 1 through Cycle 3, participants will be monitored for approximately 6 hours following XMT-1660 administration for safety assessment and PK sampling.

[0539] Initially, participants are dosed once every 3 weeks (e.g., on a 3 -week cycle) or once every 4-weeks (e.g., on a 4-week cycle). Participants may also be dosed every 5 weeks (e.g., on a 5-week cycle) or every six weeks (e.g., on a 6- week cycle).

[0540] In some cases, a split dosing regimen will be adopted, e.g., a split dosing regimen on a 28-days cycle (e.g., a 4-week cycle). In some cases, XMT-1660 will be dosed on a 4-week (e.g,, 28-day) cycle with one-half of the dose administered on day 1 of each cycle, and one-half of the dose administered on day 8 of each cycle. Thus, for example, when the dose is 59.0 mg / m2(DL.Attorney Docket No. 43704-02721 MRSN-047 / 001WO 6.5), a split-dosing regimen will administer 29.5 mg / m2on day 1 of each cycle (e.g., each 4-week cycle) and 29.5 mg / m2on day 8 of each cycle (e.g., each 4-week cycle).

[0541] In some cases, a 2Q4W dosing regimen is adopted, for example, dosing of the full indicated dose on day 1 and on day 8 of each 28-day cycle. Thus, for example, when a dose is 28.7 mg / m2is administered on a 2Q4W(dayl / day8) regimen, 28.7 mg / m2is administered on day 1 and 28,7 mg / m2is administered on day 8 of each 28 day cycle. In embodiments, if a patient’s BSA is greater than 2.0, each administration is capped at a number of mg that is 2x the indicated mg / m2dose.

[0542] Dose Modification for subsequent cycles

[0543] Dose adjustments may be made if a participant experiences toxicity but would benefit from further treatment with the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660). In such cases, treatment at a reduced dose may commence if the observed toxicity resolves to Grade 1 or Grade 2. Guidance for dose modifications related to specific events is provided below.

[0544] In some cases, altering the dose schedule (e.g., from a three-week cycle to a four-week cycle) may be implemented to mitigate potential toxicity effects in participants.Table 2 defines the dose modification actions that will be taken based on hepatotoxicity, as measured by AS T and ALT levelsTable 2Grade Description ActionGrade • If normal at basel ine: No dose adjustment is required.1 > ULN-3.0xULN• If abnormal at baseline:1.5-3. OxbaselineGrade • If normal at baseline: • Withhold XMT-1660 until toxicity resolves 2 >3.0-5.0xULN to Grade <1 or baseline, then resume at the • If abnormal at baseline: same dose level>3.0-5. Oxbaseline•Grade • If normal at basel ine:• Withhold XMT-1660 until toxicity resolves 3 >5.0-20,0xULN to Grade <1 or baseline.Attorney Docket No. 43704-02721 MRSN-047 / 001WO Grade Description Action• If abnormal at baseline: • If toxicity resolves prior to the next scheduled dosing day, no dose modification >5.0-20. Ox baselineis required.► If treatment delay is required, resume at the next lower dose level as per Table 11.Grade • If normal at baseline: Permanently discontinue XMT-1660.4 >20.0xULN• If abnormal at baseline:>20. Ox baselineAbbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.

[0545] Table 3 provides dose modification guidance for ILD / Pneumonitis

[0546] Participants will be closely monitored throughout the study to allow for the early detection of symptoms that may be indicative of ILD / pneumonitis.

[0547] Symptoms may include hypoxia, dyspnea, cough, fever, or acute worsening of a baseline pulmonary condition. A diagnostic evaluation for ILD / pneumonitis should be conducted if a participant develops radiographic changes potentially consistent with ILD / pneumonitis or develops an acute onset of new or worsening pulmonary or other related signs / symptoms such as dyspnea or cough.

[0548] Treatment considerations should include the use of corticosteroids as soon as ILD / pneumonitis is suspected. If an etiology other than ILD / pneumonitis is diagnosed, follow clinical practice.Table 3Grade Description Dose Modification ActionsGrade 1 Asymptomatic; clinical or • Withhold XMT-1660 until resolved and diagnostic observations only; resume XMT-1660 at the next lower dose as intervention not indicated per the Table 1.* Systemic steroids (e.g., at least 0.5 mg / kg / day prednisone or equivalent) may be started untilAttorney Docket No. 43704-02721 MRSN-047 / 001WO Grade Description Dose Modification Actionsimprovement, followed by gradual taper over at least 4 weeksGrade 2 Symptomatic; medical • Permanently discontinue use of XMT-1660.intervention indicated; limitinginstrumental ADLSevere symptoms; limitingGrade 3 self-care ADI.,; oxygenindicatedLife-threatening respi ratorycompromise: urgentGrade 4 intervention indicated (e.g.,tracheotomy or intubation)Abbreviations: ADL=activities of daily living; ILD=interstitial lung disease.|00549] For any new or worsening Grade 1, Grade 2 or Grade 3 corneal adverse event, withhold or delay XMT-1660 until an ocular examination indicates the AE is Grade <1.

[0550] Table 4 provides guidance for dose modification increased serum creatinine. No dose modification or management is required for Grade 1 events.Table 4Grade Description Dose Modification ActionGrade • If serum creatinine normal • Withhold XMT-1660 until toxicity resolves to 2 at baseline: >1.5-3.0*ULN Grade <1 or baseline, then resume at the same • If abnormal at baseline: dose level.>1.5-3. Oxbaseline «Grade • If serum creatinine normal • If toxicity has resolved to Grade <1 or baseline 3 at baseline: >3.0-6.0xULN prior to next scheduled dosing day, no dose • If abnormal at baseline: reduction required.>3. Ox baseline • If a treatment delay is required, WithholdAttorney Docket No.43704-02721 MRSN-047 / 001WO Grade Description Dose Modification ActionXMT- 1660 until toxicity resolves to Grade <1 or baseline and resume at next lower dose level as per the Table 1.Grade Serum creatinine >6.0*ULN Permanently discontinue XMT- 1660.4Abbreviation: ULN=upper limit of normal.Dose Modification and Management for Proteinuria

[0551] Participants will undergo dipstick urinalysis and urine albumin to creatinine ratio (uACR) measurement before each dose of XMT-1660 and at regular intervals during a dosing cycle. If proteinuria is detected by dipstick urinalysis, a repeat dipstick urinalysis and uACR measurement with clean or midstream urine collection is recommended.

[0552] For recurrent 1+ proteinuria after 2 consecutive doses of study treatment or any instance of >2+ proteinuria, a 24-hour urine collection is required; it should be obtained in enough time to have results before the next cycle (based on standard local laboratory turnaround time) to avoid unnecessary treatment delay. For Grade 3 proteinuria described in Table 5 a renal biopsy may be considered. Additionally, for any grade proteinuria, a 24-hour urine collection is required within 14 days before the first dose of each subsequent cycle.

[0553] See Table 5 for dose modification and management guidelines for participants with proteinuria.

[0554] Participants with nephrotic syndrome characterized by severe proteinuria (urinary protein >3.5 g / 24 h) together with hypoalbuminemia (albumin <3 g / dL) and peripheral edema should permanently discontinue XMT-1660.

[0555] It is strongly recommended that all participants should be started on 25 mg losartan when they receive their first dose of XMT 1660, unless medically contraindicated. If losartan is not available or is medically contraindicated, an ACE inhibitor can be substituted. The ARB or ACE inhibitor package insert should be consulted to determine if a participant is eligible to receive it. Participants should continue receiving either an ARB or ACE inhibitor as long as study treatment continues, unless treatment with the ARB or ACE inhibitor becomes intolerable. Additionally, if a participant develops chronic diarrhea or any other clinical condition that may lead to hypotension, treatment with the ARB or ACE inhibitor should be discontinued. If proteinuria does not resolve,Attorney Docket No. 43704-02721 MRSN-047 / 001WO worsens, or recurs, a sodium glucose cotransporter2 (SGLT2) inhibitor (dapagliflozin or empagliflozin) should be added. All medications should be prescribed in accordance with their product labels.Table 5Grade Description Dose Modification Action Additional Management Action Grade 1 Urinaiy protein No dose modification is required. » Consider a nephrology consultation. or Grade UI, N-<3.5 g / 24 h » Initiate appropriate medical therapy and monitor as clinically indicated.2Grade 3 Urinaiy protein » Continue treatment at the next » A nephrology consultation is >3.5 g / 24 h recommended.lower dose level (no further» Initiate, maintain, or intensify medical and serum albumin dose reductions are needed as therapy as appropriate and monitor its Grade <1 long as serum albumin and clinically indicated.and serum creatinine serum creatinine areGrade <1 Grade <1)with no clinicalsymptoms associatedwith renal dysfunctionUrinaiy' protein • Withhold XMT- 1660 until » A nephrology' consultation is required. >3.5 g / 24 h » Initiate, maintain, or intensify medical and either serum albumin and serumtherapy' as appropriate and monitor as serum albumin creatinine are both Grade <1, clinically indicated.Grade >2 then resume treatment at theor next lower dose level (noserum creatinine further dose reductions areGrade >2 needed as long as serumalbumin and serum creatinineare Grade <1)

[0556] Table 6 provides dose modification guidance for thrombocytopenia. No dose modification or management is required for Grade 1 events.Attorney Docket No.43704-02721 MRSN-047 / 001WO Table 6Grade Description Dose Modification ActionGrade Platelets <75- • If toxicity has resolved to Grade <1 or baseline prior 2 50x109 / L to next scheduled dosing day, no dose reduction required.• If a treatment delay is required, withhold XMT-1660 until toxicity resolves to Grade <1 or baseline and resume at next lower dose level as per the Table 1.Grade Platelets • Withhold XMT-1660 until toxicity resolves to3 <50-25 101’ 1. Grade <1.• XMT-1660 may be resumed at next lower dose level as per the Table 1.Grade Platelets <25x109 / L • Withhold XMT-1660 until toxicity resolves to4 Grade <1.• XMT-1660 may be resumed at next lower dose as per the Table 1.

[0557] Table 7a provides dose modification guidance for hypertension.Table 7aCriteria Definition Dose Modification ActionGrade 2 Systolic BP <160 mm No dose adjustment required.Hg and diastolic BP<100 mm Hg on morethan one assessmentGrade 3 Systolic BP >160 mm • Withhold XMT-1660.Hg or diastolic BP * If hypertension is controlled and symptomatic >10 hypertension has resolved by 4 weeks after0 mm Hg initiating anti-hypertensive therapy orOR management, XMT-1660 may be resumed at next lower dose as per the Table 1.Attorney Docket No.43704-02721 MRSN-047 / 001WO Criteria Definition Dose Modification Actionsymptomatic • If hypertension has not resolved within this hypertension CTCAE timeframe, permanently discontinue XMT-1660. Grade <4Hypertensio Life threatening Permanently discontinue XMT-1660.n Grade >4 consequences (e.g.,malignanthypertension, transientor permanentneurologic deficit,hypertensive crisis);urgent interventionindicatedAttorney Docket No.43704-02721 MRSN-047 / 001WO Dose Modification and Management for Troponin I Elevation

[0558] Table 7b provides dose modification guidance for Troponin I Elevation. See Table 7b for dose modification and management guidelines for participants with any troponin I elevation that is considered by the Investigator to be related to XMT-1660,Table 7b; Dose Modification and Management for Troponin I Elevation Grade Dose Modification Action Additional Management Action Grade 1 No dose modification is required. Initiate appropriate medical therapy and monitor as clinically indicated.Grade 3 * Withhold XMT- 1660 unti 1resolution to Grade <1.« Contact the study Medical Monitorbefore resuming XMT-1660 ateither the same or next lower doselevel at the discretion of theInvestigator.AnalysesSafety Analysis

[0559] At the end of DES, the MTD will be selected as the dose for which the isotonic estimate of the DLT probability is closest to the target DET rate. The isotonic estimates of the DLT probabilities will be obtained using the pooled adjacent violators algorithm. The number and percentage of participants who experienced a DLT by dose level and across all dose levels in DES will be reported. Participants completing Cycle 1 in the absence of a DLT will be considered to have tolerated the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) regimen. The number and percentage of participants who tolerated the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) regimen will be reported by dose level and across all dose levels in the subset of participants evaluable for assessment of tolerability in DES. All AEs and AECIs will be reported by dose level and across all dose levels in DES. All AEs and AECIs will be reported by cancer population and, if applicable, by dose level and across all dose levels, in the Backfill Cohorts and EXP. The seriousness, CTC E severity grading, and Investigator-reported relationship of AEs to study treatment will be summarized and listed. Safety' laboratory data will be summarized and listed.

[0560] Efficacy AnalysisAttorney Docket No. 43704-02721 MRSN-047 / 001WO

[0561] Tumor responses assessed by the Investigator per RECIST version 1.1 will be used to perform the following efficacy analyses: (1) ORR: defined as the percentage of participants who achieve a best overall response of confirmed CR or PR, The number and percentage of participants achieving a confirmed response will be summarized and an exact 95% CI will be provided; (2) DOR: defined as the time from when response criteria are first met until disease progression or death m participants who achieve confirmed CR or PR. Kaplan-Meier estimates of medians and quartiles with 95% Cis will be reported; and (3) DCR: defined as the percentage of participants who achieve CR, PR, or stable disease as the result of study treatment. The number and percentage of participants achieving response or disease control will be summarized and an exact 95% CI will be provided.

[0562] In addition, efficacy will be assessed in participant groups based on the level of B7-114 expression in tumors. B7-H4 expression status will be confirmed as described below, and ORR, DOR, and DCR (with associated Cis) will be reported by participants stratified by B7-H4 status. B7-H4 expression is determined based on a B7-H7 immunohistochemistry assay measuring tumor cell plasma membrane staining of B7-H4. Results are expressed as a Tumor Proportion Score (TPS), where the TPS cut-offs of low, medium, and high plasma membrane staining will be used group the participants. Thus, m embodiments, patient B7-H4 expression is used prospectively to identify and treat patients most likely to respond to therapy with the B7-H4-targeted antibody-drug conjugate. In embodiments, treatment involves identifying a subject having cancer and having a tumor with high or medium B7-H7 TPS (or, alternatively, a high B7-H4 TPS), and subsequently treating said identified patient with a B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) as described herein.Pharmacokinetic Analysis

[0563] The PK profiles of the active moieties, release products, and selected metabolites of the B7-H4-targeted antibody-drug conjugate (e.g., XMT-1660) will be determined for each participant by non-compartmental analysis (NCA) with validated PK software (i.e. Phoenix WinNonlin). PK parameters per participant will include Cmax, time of maximum observed concentration (tmax), and area under the concentration-time curve for the last measurable concentration (AUCo-iast), as data permit. When the terminal elimination phase can be identified, additional parameters such as terminal elimination half-life (tv), clearance (CL), volume of distribution (Vss), and area under the concentration-time curve to infinity (AUCo-00) will beAttorney Docket No.43704-02721 MRSN-047 / 001WO determined, as data permit. The accumulation ratio of Cmax and AUC will be calculated for all components after multiple doses, as appropriate.

[0564] The handling of missing concentration and covariate data, outliers, and values below the limit of quantification will be provided in separate Clinical Pharmacology Analysis Plans for NCA and population PK analysis. The modeling for dose / exposure-response and relationships will be completed with appropriate nonlinear mixed effect software (e.g, NONMEM) and provided in a separate Clinical Pharmacology Analysis Plan. The results of such analyses, if conducted, may be provided in a separate report.Example 2: Tumor Growth Response to Administration of XMT-1660 in CTG-1280 Patient Derived Endometrial Cancer Xenograft Mouse Model

[0565] Female athymic nude mice were implanted sub...

Claims

Attorney Docket No. 43704-02721 MRSN-047 / 001WO What is claimed is:1, A method of treating cancer in a subject in need thereof, comprising administering to the subject a B7-H4-targeted antibody-drug conjugateof Formula (I):(I) whereini. di3 is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRII3 ) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region I (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chainAttorney Docket No.43704-02721 MRSN-047 / 001WO complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7),lii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; andiv. ■ is GlcNAc; is Fuc; and > is GalNAc; and wherein the subject(a) has not received a vascular endothelial growth factor (VEGF)-targeted therapy;(b) does not have or has a prior history of proteinuria requiring therapeutic intervention, including delay or discontinuation of a prior anticancer therapy;and / or(c) has a urine protein concentration of less than or equal to 500 mg within 14 days prior to administration of the B7-H4-targeted antibody-drug conjugate.

2. The method of claim 1, wherein the VEGF-targeted therapy comprises bevacizumab, ramucirumab, pegaptanib, ranibizumab, aflibercept, conbercept, brolucizumab, or faricimab.3, A method of treating cancer in a subject in need thereof, comprising administering to the subject an angiotensin converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB), and a B7-H4-targeted antibody-drug conjugate of Formula (I):Attorney Docket No.43704-02721 MRSN-047 / 001WONH(I) whereini. di3 is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRE1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the ammo acid sequence QQYGSSPLYT (SEQ ID NO: 7),lii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; andiv. ™is GlcNAc; is Fuc; and I — I is GalNAc.Attorney Docket No.43704-02721 MRSN-047 / 001WO4. The method of claim 3, wherein the ACE inhibitor and / or ARB is titrated to normal blood pressure.

5. The method of claim 3 or 4, further comprising administering the subject a sodium-glucose co-transporter 2 (SGLT2) inhibitor.

6. A method of treating cancer in a subject, comprising administering to the subject a sodiumglucose co-transporter 2 (SGLT2) inhibitor;and a B7-H4-targeted antibody-drug conjugate of Formula (I):(I) whereini. di3 is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the ammo acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acidAttorney Docket No.43704-02721 MRSN-047 / 001WO sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1 ) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7),iii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered m accordance with EU numbering; andiv. ■ is GlcNAc; is Fuc; and > is GalNAc.

7. A method of decreasing the incidence or seventy of proteinuria in a subject having cancer and receiving a B7-H4-targeted antibody-drug conjugate, comprising administering (a) an ACE inhibitor and / or an ARB and / or (b) a SGLT2 inhibitor;wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):ANTIBODY / / O IIAttorney Docket No.43704-02721 MRSN-047 / 001WO (I)whereini. dis is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the ammo acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRII3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRLl) comprising the ammo acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the ammo acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7),iii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; andiv. ■ is GlcNAc; is Fuc; and > is GalNAc.

8. The method of claim 7, wherein the ACE inhibitor and / or ARB is titrated to normal blood pressure.

9. The method of any one of claims 6-8, wherein the SGLT2 inhibitor is dapagliflozin or empagliflozin.

10. The method of any one of claims 3-9, wherein the ARB is azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan or valsartan.

11. The method of claim 10, wherein losartan is administered at a dosage of about 25 mg to about 100 mg once daily.

12. The method of claim 11, wherein the losartan is administered at a dosage of about 25 mg once daily.Attorney Docket No.43704-02721 MRSN-047 / 001WO13. The method of any one of claims 3-12, wherein the administration of the ARB and / or the ACE inhibitor is initiated prior to or at the same time as the first administration of the B7-H4-targeted antibody-drug conjugate.

14. The method of claim 13, wherein the admistration of ARB and or the ACE inhibitor is continued throughout the period of treatment with the B7-H4-targeted antibody-drug conj ugate.

15. The method of any one of claims 3-14, wherein the ACE inhibitor is benazepril, captopril, enalapril, fosinopnl, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

16. The method claim 3, father comprising treating the subject with a SGLT2 inhibitor if the subject develops proteinuria during treatment.

17. The method of any one of claims 1-16, wherein the antibody comprises a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 8.

18. The method of any one of claims 1-17, wherein the antibody comprises 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: 12.

19. The method of any one of claims 1-18, wherein the B7-H4-targeted antibody-drug conjugate is administered by infusion at a dose of between about 38.1 mg / m2to about 115.0 mg / m2.

20. The method of any one of claims 1-19, wherein the B7-H4-targeted antibody-drug conjugate is administered at a dose of:about 37,6 mg / m2to about 38,6 mg / m2,about 44.0 mg / m2to about 45.0 mg / m2,about 50,2 mg / m2to about 51.2 mg / m2,about 58.5 mg / m2to about 59.5 mg / m2,Attorney Docket No.43704-02721 MRSN-047 / 001WO about 66.9 mg / m2to about 67.9 mg / m2,about 77.0 mg / m2to about 78.0 mg / m2,about 79,5 mg / m2to about 80,5 mg / m2,about 87.1 mg / m2to about 88.1 mg / m2,about 94,5 mg / m2to about 95,5 mg / m2, orabout 114.5 mg / m2to about 115.5 mg / m2.

21. The method of any one of claims 1 -20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 38.1 mg / m2.

22. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 44.5 mg / m2.

23. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 50.7 mg / m2.

24. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 59.0 mg / m2.

25. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 67.4 mg / m2.

26. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 77.5 mg / m2.

27. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 80.0 mg / m2.

28. The method of any one of claims 1 -20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 87.6 mg / m2.Attorney Docket No.43704-02721 MRSN-047 / 001WO 29. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 95.0 mg / m2.

30. The method of any one of claims 1-20, wherein the B7-H4-targeted antibody-drug conjugate dose is administered at a dose of about 115.0 mg / m2.

31. The method of any one of claims 19-30, wherein if the subject’s body surface area is calculated to be greater than 2.0 m2, the subject is administered a dose calculated based on a body surface area of about 2.0 m2.

32. The method of any one of claims 19-31, wherein the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 3 weeks thereafter.

33. The method of any one of claims 19-31, wherein the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 4 weeks thereafter.

34. The method of any one of claims 19-31, wherein the administration of the B7-H4-targeted antibody-drug conjugate is performed on day 1 of treatment, and every 6 weeks thereafter.

35. The method of any one of claims 19-31, wherein the dose of the B7-H4-targeted antibodydrug conjugate is administered on day 1 and is administered on day 8 of a treatment cycle, optionally wherein the cycle is a 4-week treatment cycle (e.g., is administered on a dld8 q2w4 dosing schedule).

36. The method of any one of claims 1-35, wherein the cancer is B7-H4-positive, optionally as measured by tumor proportion score (TPS).

37. The method of any one of claims 1 -36, wherein the TPS is greater than or equal to 50%.

38. The method of any one of claims 1 -36, wherein the TPS is greater than or equal to 70%.Attorney Docket No.43704-02721 MRSN-047 / 001WO 39. The method of any one of claims 1-38, wherein the cancer is adenoid cystic carcinoma (ACC), breast cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

40. The method of claim 39, wherein the cancer is breast cancer.

41. The method of claim 40, wherein the breast cancer is HER2 negative breast cancer, for example, is triple negative breast cancer (TNBC) or hormone receptor positive / HER2 negative (HR+ / HER2-) breast cancer.

42. The method of claim 39, wherein the cancer is endometrial cancer.

43. The method of claim 39, wherein the cancer is ovarian cancer.

44. The method of claim 39, wherein the cancer is ACC.

45. The method of 44, wherein the ACC is ACC Type I.

46. The method of 44, wherein the ACC is ACC Type II.

47. The method of any one of claims 39 and 44-46, wherein the subject with ACC is identified for treatment by (a) identification of an activating mutation a Notch pathway gene (e.g., NOTCH-1, NOTCH-2, NOTCH-3, or NOTCH-4), optionally in the NOTCH- 1 gene, optionally as identified by next-generation sequencing (NGS); and / or (b) a tumor biopsy testing positive for c-MYC and / or negative or low-expressing for TP63, optionally as measured by immunohistochemistry (IHC).

48. The method of any one of claims 39 and 44-46, wherein the subject with ACC is identified for treatment by having a clinical course characterized by <3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with atypical sites of metastases (e.g. bone, CNS, and non-pulmonary or -hepatic viscera) and a solid tumor morphology on histologic evaluation.Attorney Docket No.43704-02721 MRSN-047 / 001WO 49. The method of any one of claims 39-41, wherein the subject that has TNBC has received at least 1 line of systemic therapy in a locally advanced or metastatic breast cancer setting.

50. The method of any one of claims 39-41, wherein the subject that has HR+ / HER2- breast cancer has received at least one line of systemic therapy which must have included CDK 4 / 6 inhibitor and endocrine therapy (ET), in an advanced or metastatic breast cancer setting.

51. The method of any one of claims 39-41, wherein the subject that has HR+ZHER2- breast with tumor expression of both progesterone receptor and estrogen receptor >10% by IHC are required to receive CDK4 / 6 inhibitor and endocrine-based therapy.

52. The method of any one of claims 39 and 42, wherein the subject that has endometrial cancer has received at least 1 line of systemic therapy including platinum-based chemotherapy for advanced or metastatic disease.

53. The method of any one of claims 39 and 43, wherein the subject that has ovarian cancer, fallopian tube cancer, or primary peritoneal cancer has received at least 1 line of systemic therapy for advanced or metastatic disease including platinum-based chemotherapy.

54. The method of any one of the preceding claims, wherein the subject is human.

55. The method of any one of the preceding claims, wherein the B7-H4-targeted antibody drug conjugate is administered in combination with an immune checkpoint inhibitor molecule, optionally wherein the immune checkpoint inhibitor molecule is a PD-l-binding molecule, e g., an anti-PD-1 antibody, or a PD-L1 -binding molecule, e g., an anti-PD-Ll antibody.

56. The method of claim 55, wherein the B7-H4-targeted antibody drug conjugate and the immune checkpoint inhibitor molecule are administered concurrently or sequentially.Attorney Docket No.43704-02721 MRSN-047 / 001WO 57. The method of any one of the preceding claims, wherein the B7-H4-targeted antibody drug conjugate is administered to a subject who has received prior therapy comprising a topoisomerase 1 inhibitor-containing antibody drug conjugate.

58. The method of claim 57, wherein the cancer has become resistant to or not responsive to therapy with the topoisomerase 1 inhibitor-containing antibody drug conjugate (optionally wherein the resistance is caused by resistance to the topoisomerase I inhibitor).

59. The method of any one of claims 57 or 58, wherein the cancer has progressed following therapy with the topoisomerase 1 inhibitor-containing antibody drug conjugate but prior to administration of the B7-H4-targeted antibody drug conjugate.

60. A B7-H4-targeted antibody drug conjugate for use in combination with an ACE inhibitor and / or an ARB for the treatment of cancer in a subject;wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (1):(I)Attorney Docket No.43704-02721 MRSN-047 / 001WO whereini. di3 is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRII3 ) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region I (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the ammo acid sequence QQYGSSPLYT (SEQ ID NO: 7),lii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; andiv. ■ is GlcNAc; is Fuc; and > is GalNAc.

61. A B7-H4-targeted antibody drug conjugate for use in combination with a SGLT2 inhibitor for the treatment of cancer in a subject;wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):Attorney Docket No.43704-02721 MRSN-047 / 001WOANTIBODYwhereini. di3 is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRE1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the ammo acid sequence QQYGSSPLYT (SEQ ID NO: 7),lii. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; and■ A nis GlcNAc; AX is Fuc; and1— ' is GalNAc.Attorney Docket No.43704-02721 MRSN-047 / 001WO62, An ACE inhibitor and / or an ARB, for use in combination with a B7-H4-targeted antibodydrug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated with a B7-H4-targeted antibody-drug conjugate;wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):ANTIBODY(i) whereini. di3 is about 2;li. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRHI) comprising the amino acid sequence GFIVSRNY (SEQ ID NO: 2), a variable heavy chain complementarity determining region 2 (CDRH2) comprising the ammo acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRII3 ) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region I (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2)Attorney Docket No.43704-02721 MRSN-047 / 001WO comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQYGSSPLYT (SEQ ID NO: 7),iii. the Drug is attached to a heavy chain of the antibody via a linker moiety' at an asparagine residue at position 297 when numbered in accordance with EU numbering; and■ A I — 1is GlcNAc; AX is Fuc; and1— > is GalNAc.

63. An SGLT2 inhibitor, for use in combination with a B7-H4-targeted antibody-drug conjugate for the treatment of cancer in a subject and / or decreasing the incidence or severity of proteinuria in a subject having cancer and being treated with a B7-H4-targeted antibody-drug conjugate; wherein the B7-H4-targeted antibody-drug conjugate is a conjugate of Formula (I):(I) whereini. d is about 2;ii. the ANTIBODY binds B7-H4 and comprises a variable heavy chain complementarity determining region 1 (CDRHl) comprising the ammo acid sequence GFIVSRNY (SEQ ID NO: 2),Attorney Docket No.43704-02721 MRSN-047 / 001WO a variable heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence IYGSGRT (SEQ ID NO: 3), a variable heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence ARDADYGLDV (SEQ ID NO: 4), a variable light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence QSVSSSY (SEQ ID NO: 5), a variable light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence GAS (SEQ ID NO: 6), and a variable light chain complementarity determining region 3 (CDRL3) comprising the ammo acid sequence QQYGSSPLYT (SEQ ID NO: 7),hi. the Drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 297 when numbered in accordance with EU numbering; andiv. ■is GlcNAc; is Fuc; and t— 3 is GalNAc.

64. The method, B7-H4-targeted antibody drug conjugate for use, ACE inhibitor and / or ARB for use, or SGLT2 inhibitor for use of any one of the preceding claims, wherein the B7-H4-targeted antibody drug conjugate is emiltatug ledadotin.

65. The method, B7-H4-targeted antibody drug conjugate for use, ACE inhibitor and / or ARB for use, or SGLT2 inhibitor for use of any one of the preceding claims, wherein the ACE inhibitor, ARB and / or SGLT2 inhibitor reduce or prevent proteinuria in said subject.

66. A kit comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an ACE inhibitor and / or an ARB, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.

67. A kit comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an SGLT2 inhibitor, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.

68. A kit comprising: (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.Attorney Docket No.43704-02721 MRSN-047 / 001WO 69. A pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an ACE inhibitor and / or an ARB, for use in combination, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.

70. A pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate and (b) an SGLT2 inhibitor for use in combination, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.

71. A pharmaceutical composition comprising: (a) a B7-H4-targeted antibody-drug conjugate, (b) an ACE inhibitor and / or an ARB, and (c) an SGLT2 inhibitor for use in combination, wherein the B7-H4-targeted antibody-drug conjugate is as defined in any one of claims 1 and 17-18.

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