# US 11,440,969 B2 · Use of human epididymis protein 4 (HE4) for assessing responsiveness of MUC 16-positive cancer treatment

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- Number: US 11,440,969 B2
- Document ID: US11440969B2
- Status: Granted
- Kind: B2
- Application number: 16/239,663
- Filed: 2019-01-04
- Published: 2019-08-01
- Granted: 2022-09-13
- Earliest claimed: 2016-07-08
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Mark Lackner; Daniel Maslyar; Yulei Wang; Walter Darbonne; Eric Humke
- Web page: https://patentgrep.com/patent/US11440969B2

## CPC

- C07K 16/3092: {against tumour-associated mucins}
- A61K 31/22: of acyclic acids, e.g. pravastatin
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6817: {Toxins}
- A61K 47/6859: {the tumour determinant being from liver or pancreas cancer cell}
- A61K 47/6869: {the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate}
- A61P 35/00: Antineoplastic agents
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- G01N 33/57545: of the ovaries
- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- G01N 33/5758: {involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- 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)
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention relates to methods and kits or articles of manufacture related thereto that may find use, inter alia, in assessing responsiveness of cancers to MUC16 antagonists by monitoring HE4 expression. In some embodiments, the methods include measuring the level of expression of HE4 in a sample from a subject; comparing the level of expression of HE4 in the sample with the level of expression of HE4 in a sample previously obtained from the subject; and, optionally, administering to the subject a therapeutically effective amount of a MUC16 antagonist.

## Claims

### Claim 1

A method for treating or delaying progression of a MUC16-positive cancer in a subject in need thereof, the method comprising:
(a) measuring the expression level of human epididymis protein 4 (HE4) in a sample obtained from the subject at a first time point, wherein the first time point is prior to administering to the subject a MUC16 antagonist;
(b) administering to the subject a therapeutically effective amount of the MUC16 antagonist; and
(c) measuring the expression level of HE4 in a sample obtained from the subject at a second time point, wherein the second time point is after administration of the MUC16 antagonist, and
wherein the subject is administered one or more additional therapeutically effective amounts of the MUC16 antagonist if the expression level of HE4 at the second time point is at least 25% lower than the expression level of HE4 at the first time point.

### Claim 2 (depends on 1)

The method of claim 1, further comprising step (d): administering to the subject the one or more additional therapeutically effective amounts of the MUC16 antagonist when the expression level of HE4 at the second time point is at least 25% lower than the expression level of HE4 at the first time point.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject has never received the MUC16 antagonist.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is undergoing treatment with the MUC16 antagonist.

### Claim 5

A method for treating or delaying progression of a MUC16-positive cancer in a subject in need thereof, the method comprising administering to the subject one or more therapeutically effective amounts of a MUC16 antagonist, wherein an initial therapeutically effective amount of the MUC16 antagonist was administered prior to administration of the one or more therapeutically effective amounts of the MUC16 antagonist, and:
wherein a sample obtained from the subject after administration of the initial therapeutically effective amount of the MUC16 antagonist was determined to have an epididymis protein 4 (HE4) expression level that is at least 25% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
wherein the subject was selected for treatment based on a determination that a sample obtained from the subject after administration of the initial therapeutically effective amount of the MUC16 antagonist has an epididymis protein 4 (HE4) expression level that is at least 25% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
wherein treatment is based upon the subject having a sample that expresses epididymis protein 4 (HE4) at a level that is at least 25% lower after administration of the initial therapeutically effective amount of the MUC16 antagonist than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
provided that the subject has been found to have a sample that expresses epididymis protein 4 (HE4) at a level that is at least 25% lower after administration of the initial therapeutically effective amount of the MUC16 antagonist than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist.

### Claim 6 (depends on 1)

The method of claim 1, further comprising administering a second treatment therapy to the subject.

### Claim 7 (depends on 1)

The method of claim 1, wherein:
the first time point occurs at least 3 days before, at least 1 day before, at least 12 hours before, at least 4 hours before, at least 1 hour before, less than 1 hour before, or immediately before administering the therapeutically effective amount of the MUC16 antagonist; and/or
the second time point occurs at least 1 hour after, at least 4 hours after, at least 12 hours after, at least 1 day after, at least 3 days after, at least 5 days after, at least 1 week after, at least 2 weeks after, or at least 3 weeks after administering the therapeutically effective amount of the MUC16 antagonist.

### Claim 8 (depends on 1)

The method of claim 1, wherein the sample is a blood sample, a serum sample, or a cell sample.

### Claim 9 (depends on 1)

The method of claim 1, wherein the expression level of HE4 is circulating level of HE4 protein, protein expression level of HE4, or RNA transcript level of HE4.

### Claim 10 (depends on 1)

The method of claim 1, wherein the subject is administered one or more additional therapeutically effective amounts of the MUC16 antagonist if the expression level of HE4 at the second time point is at least 40% lower than the expression level of HE4 at the first time point.

### Claim 11 (depends on 1)

The method of claim 1, wherein the MUC16-positive cancer is selected from the group consisting of ovarian cancer, endometrial cancer, triple-negative breast cancer, pancreatic cancer, and non-small cell lung cancer.

### Claim 12 (depends on 1)

The method of claim 1, wherein the MUC16-positive cancer is unresectable pancreatic cancer.

### Claim 13 (depends on 1)

The method of claim 1, wherein the MUC16-positive cancer is an ovarian cancer selected from the group consisting of primary peritoneal carcinoma, epithelial ovarian carcinoma, metastatic ovarian cancer, fallopian tube carcinoma, and platinum-resistant ovarian cancer.

### Claim 14 (depends on 1)

The method of claim 1, wherein the MUC16 antagonist is selected from the group consisting of an anti-MUC16 antibody, a MUC16 inhibitor, a protein, a peptide, a fusion protein, and an immunoadhesin.

### Claim 15 (depends on 1)

The method of claim 1, wherein the MUC16 antagonist is an anti-MUC16 antibody.

### Claim 16 (depends on 15)

The method of claim 15, wherein the anti-MUC16 antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain, or the light chain variable domain, or both comprise the following HVRs:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4;
(b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 5;
(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 6;
(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 1;
(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and
(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 3.

### Claim 17 (depends on 15)

The method of claim 15, wherein the anti-MUC16 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8, or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, or both.

### Claim 18 (depends on 15)

The method of claim 15, wherein the anti-MUC16 antibody is an antibody fragment selected from a Fab, Fab′-SH, Fv, scFv, or F(ab′)2.

### Claim 19 (depends on 15)

The method of claim 15, wherein one or more amino acid residues are replaced with one or more free cysteine amino acids having a thiol reactivity in the range of 0.6 to 1.0.

### Claim 20 (depends on 19)

The method of claim 19, wherein the antibody comprises a cysteine at one or more positions selected from 15, 43, 110, 144, 149, 168 and 205 of the light chain according to Kabat numbering convention and 41, 88, 115, 118, 120, 171, 172, 282, 375, and 400 of the heavy chain according to EU numbering convention.

### Claim 21 (depends on 15)

The method of claim 15, wherein the anti-MUC16 antibody is covalently attached to a cytotoxic agent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the anti-MUC16 antibody is covalently attached to the cytotoxic agent through a linker and the linker comprises one or more of 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2-pyridylthio) pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate (SMCC), N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB), and 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB).

### Claim 23 (depends on 22)

The method of claim 22, wherein the linker is attached to the antibody through a thiol group on the antibody.

### Claim 24 (depends on 21)

The method of claim 21, wherein the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

### Claim 25 (depends on 1)

The method of claim 1, wherein the MUC16-positive cancer is a platinum-resistant ovarian cancer.

### Claim 26 (depends on 5)

The method of claim 5, wherein the MUC16-positive cancer is a platinum-resistant ovarian cancer.

### Claim 27 (depends on 1)

The method of claim 1, wherein the subject is administered one or more additional therapeutically effective amounts of the MUC16 antagonist if the expression level of HE4 at the second time point is at least 25% to up to 45% lower than the expression level of HE4 at the first time point.

### Claim 28 (depends on 5)

The method of claim 5, wherein:
a sample obtained from the subject after administration of the initial therapeutically effective amount of a MUC16 antagonist was determined to have an epididymis protein 4 (HE4) expression level that is at least 25% to up to 45% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
the subject was selected for treatment based on a determination that a sample obtained from the subject after administration of the initial therapeutically effective amount of the MUC16 antagonist has an epididymis protein 4 (HE4) expression level that is at least 25% to up to 45% lower than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
treatment is based upon the subject having a sample that expresses epididymis protein 4 (HE4) at a level that is at least 25% to up to 45% lower after administration of the initial therapeutically effective amount of the MUC16 antagonist than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist; or
provided that the subject has been found to have a sample that expresses epididymis protein 4 (HE4) at a level that is at least 25% to up to 45% lower after administration of the initial therapeutically effective amount of the MUC16 antagonist than the expression level of HE4 in a sample obtained from the subject prior to administration of the initial therapeutically effective amount of the MUC16 antagonist.