# US 2014/0154273 A1 · Anthracycline-Antibody Conjugates for Cancer Therapy

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- Number: US 2014/0154273 A1
- Document ID: US20140154273A1
- Status: Published application
- Kind: A1
- Application number: 14/038,267
- Filed: 2013-09-26
- Published: 2014-06-05
- Earliest claimed: 2002-03-01
- Assignees: Immunomedics, Inc.
- Applicants: Immunomedics, Inc.
- Inventors: Gary L. Griffiths; Hans J. Hansen; Zhengxing Qu; David M. Goldenberg
- Web page: https://patentgrep.com/patent/US20140154273A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 47/6809: {Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 35/00: Antineoplastic agents
- C07H 17/00: Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- C07K 16/18: against material from animals or humans
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- 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
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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

The invention relates to therapeutic conjugates with the ability to target various antigens. The conjugates contain a targeting antibody or antigen binding fragment thereof and an anthracycline chemotherapeutic drug. The targeting antibody and the chemotherapeutic drug are linked via a linker comprising a hydrazide moiety.

## Claims

### Claim 1

A method of treating a CD74-expressing cancer, comprising administering to a human subject in need thereof a conjugate of an anthracycline drug and a humanized anti-CD74 antibody or antigen-binding fragment thereof comprising human antibody framework (FR) and constant region sequences, wherein the humanized anti-CD74 antibody or antigen-binding fragment thereof is a humanized LL1 antibody or antigen-binding fragment thereof comprising light chain CDR1 having an amino acid sequence of RSSQSLVHRNGNTYLH (SEQ ID NO:1), CDR2 having an amino acid sequence of TVSNRFS (SEQ ID NO:2) and CDR3 having an amino acid sequence of SQSSHVPPT) SEQ ID NO:3) and heavy chain CDR1 having an amino acid sequence of NYGVN (SEQ ID NO:4), CDR2 having an amino acid sequence of WINPNTGEPTFDDDFKG (SEQ ID NO:5), and CDR3 having an amino acid sequence of SRGKNEAWFAY (SEQ ID NO:6), wherein the humanized anti-CD74 antibody comprises one or more substituted FR residues selected from the group consisting of light chain variable region amino acid residues 2, 3, 4, 46, 87 and 100 of SEQ ID NO:11 and heavy chain variable region amino acid residues 5, 37, 38, 46, 68, 91 and 93 of SEQ ID NO:8.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anthracycline drug is conjugated to the antibody or fragment thereof with 4-(N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide.

### Claim 3 (depends on 1)

The method of claim 1, wherein the humanized anti-CD74 antibody comprises all of the light chain variable region amino acid residues 2, 3, 4, 46, 87 and 100 of SEQ ID NO:11 and heavy chain variable region amino acid residues 5, 37, 38, 46, 68, 91 and 93 of SEQ ID NO:8.

### Claim 4 (depends on 1)

The method of claim 1, wherein the humanized anti-CD74 antibody comprises the variable region amino acid sequences of SEQ ID NO:9 and SEQ ID NO:12.

### Claim 5 (depends on 1)

The method of claim 1, wherein the humanized antibody comprises human antibody constant region sequences selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

### Claim 6 (depends on 1)

The method of claim 1, wherein said anthracycline drug is selected from the group consisting of daunorubicin, doxorubicin, epirubicin, 2-pyrrolinodoxorubicin, morpholino-doxorubicin, and cyanomorpholino-doxorubicin.

### Claim 7 (depends on 1)

The method of claim 1, wherein said anthracycline drug is linked to the antibody through the 13-keto moiety.

### Claim 8 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of B-cell lymphoma, B-cell leukemia, multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, breast cancer, lung cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, colon cancer, pancreatic cancer and melanoma.

### Claim 9 (depends on 1)

The method of claim 1, wherein the conjugate has the formula:
wherein R is either a hydrogen atom or a C1-C6 alkyl group optionally substituted with a hydroxyl group, mAb is a monoclonal antibody or antigen-binding fragment thereof and n is between 6 and 10.