# US 2017/0281791 A1 · Anti-trop-2 antibody-drug conjugates and uses thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2017/0281791 A1
- Document ID: US20170281791A1
- Status: Published application
- Kind: A1
- Application number: 15/606,447
- Filed: 2017-05-26
- Published: 2017-10-05
- Earliest claimed: 2002-03-01
- Assignees: Immunomedics, Inc.
- Applicants: Immunomedics, Inc.
- Inventors: Serengulam V. Govindan; David M. Goldenberg
- Web page: https://patentgrep.com/patent/US20170281791A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates}
- A61K 47/68037: {the drug being a camptothecin [CPT] or derivatives}
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 51/1045: {against animal or human tumor cells or tumor cell determinants}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- C07K 16/3092: {against tumour-associated mucins}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Described herein are compositions and methods of use of antibody-drug conjugates (ADCs) comprising an anti-Trop-2 antibody or antigen-binding fragment thereof, conjugated to one or more cytotoxic drugs. Preferably, the antibody is an RS7, 162-46.2 or MAB650 antibody. More preferably, the antibody is humanized. Preferably the drug is SN-38, pro-2-pyrrolinodoxorubicin, paclitaxel, calichemicin, DM1, DM3, DM4, MMAE, MMAD or MMAF. The compositions and methods are of use to treat Trop-2 expressing cancers, such as breast, ovarian, cervical, endometrial, lung, prostate, colon, stomach, esophageal, bladder, renal, pancreatic, thyroid, epithelial or head-and-neck cancer. Preferably, the cancer is one that is resistant to one or more standard cancer therapies. More preferably, the anti-Trop-2 antibody binds to Trop-2 expressed on normal cells, but administration of the anti-Trop-2 ADC to human cancer patients at a therapeutically effective dosage produces only limited toxicity.

## Claims

### Claim 1

A composition comprising an antibody-drug conjugate (ADC) comprising (i) an anti-Trop-2 antibody or antigen-binding fragment thereof; and (ii) a cytotoxic drug conjugated to the anti-Trop-2 antibody or antibody fragment.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the anti-Trop-2 antibody is a humanized or human antibody.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the anti-Trop-2 antibody is selected from the group consisting of hRS7, 162-46.2, MAB650, K5-70, K5-107, K5-116-2-1, T6-16, T5-86, BR110, 3E9, 6G11, 7E6, 15E2, 18B1, 77220, KM4097, KM4590, A1, A4, and 162-25.3; or wherein the antibody is produced by a hybridoma selected from the group consisting of AR47A6.4.2, AR52A301.5, PTA-12871, PTA-12872, PD 08019, PD 08020, and PD 08021.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the anti-Trop-2 antibody is selected from the group consisting of hRS7, 162-46.2 and MAB650.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the antibody allotype is selected from the group consisting of nG1m1, G1m3, G1m3,1, G13,2, G1m3,1,2, and Km3.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the drug is selected from the group consisting of an anthracycline, a camptothecin, a tubulin inhibitor, a maytansinoid, a calicheamycin, an auristatin, a nitrogen mustard, an ethylenimine derivative, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a taxane, a COX-2 inhibitor, a pyrimidine analog, a purine analog, an antibiotic, an enzyme inhibitor, an epipodophyllotoxin, a platinum coordination complex, a vinca alkaloid, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, a hormone antagonist, an antimetabolite, an alkylating agent, an antimitotic, an anti-angiogenic agent, a tyrosine kinase inhibitor, an mTOR inhibitor, a heat shock protein (HSP90) inhibitor, a proteosome inhibitor, an HDAC inhibitor, and a pro-apoptotic agent.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatin, COX-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, DM1, DM3, DM4, doxorubicin, 2-pyrrolinodoxorubicine (2-PDox), a pro-drug form of 2-PDox (pro-2-PDox), cyano-morpholino doxorubicin, doxorubicin glucuronide, endostatin, epirubicin glucuronide, erlotinib, estramustine, epipodophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, monomethylauristatin F (MMAF), monomethylauristatin D (MMAD), monomethylauristatin E (MMAE), navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, SN-38, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the drug is selected from the group consisting of SN-38, pro-2-pyrrolinodoxorubicin (pro-2-PDox), paclitaxel, calichemicin, DM1, DM3, DM4, MMAE, MMAD and MMAF.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the drug is SN-38.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is between 1 and 12.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is between 1.5 and 8.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is between 1 and 6.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is less than 6.

### Claim 15 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is 6 or greater.

### Claim 16 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is between 6 and 8.

### Claim 17 (depends on 1)

The composition of claim 1, wherein the average ratio of drug to antibody is between 7 and 8.

### Claim 18 (depends on 1)

The composition of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab′)2, Fab′, Fab, Fv, scFv, single-domain antibody and IgG4 half-molecule.

### Claim 19 (depends on 1)

The composition of claim 1, wherein the anti-Trop-2 antibody or fragment thereof comprises the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 1); CDR2 (SASYRYT, SEQ ID NO:2); and CDR3 (QQHYITPLT, SEQ ID NO:3) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:4); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO:5) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:6).

### Claim 20 (depends on 1)

The composition of claim 1, wherein the anti-Trop-2 antibody or fragment thereof binds to the same epitope as an anti-Trop-2 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 1); CDR2 (SASYRYT, SEQ ID NO:2); and CDR3 (QQHYITPLT, SEQ ID NO:3) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:4); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO:5) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:6).

### Claim 21 (depends on 1)

The composition of claim 1, further comprising a therapeutic agent selected from the group consisting of an immunomodulator, a cytokine, a chemotherapeutic agent, a pro-apoptotic agent, an anti-angiogenic agent, a cytotoxic agent, a drug, a second antibody, an antigen-binding fragment of a second antibody, and an immunoconjugate.