Biomarker signature for predicting tumor response to anti-CD200 therapy

Patent metadata

Field	Value
Publication number	US-11761963-B2
Application number	US-201816648503-A
Country	US
Kind code	B2
Filing date	Sep 26, 2018
Priority date	Sep 27, 2017
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

Provided herein are methods for treating cancer in a patient who has been determined to have positive expression of CD200 receptor (CD200R1) and one or more biomarkers (i.e., ICOS, TIGIT, TNFRSF9, HAVCR2, PDCD1, FCGR2A, FCGR1A, CD163, and/or CD14) by administering to the patient a CD200 inhibitor. Also provided are methods for monitoring responsiveness of a patient having cancer to treatment with a CD200 inhibitor, the method comprising: determining expression levels of CD200R1 and one or more biomarkers (i.e., ICOS, TIGIT, TNFRSF9, HAVCR2, PDCD1, FCGR2A, FCGR1A, CD163, and/or CD14) in a biological sample from the patient, wherein increased expression levels of CD200R1 and the one or more biomarkers, as compared to expression levels in a biological sample of the same type obtained from the subject prior to treatment with the CD200 inhibitor, indicates that the subject is responsive to treatment with the CD200 inhibitor.

First claim

What is claimed is:

1. A method for treating a patient having cancer who has been determined to have positive expression of CD200 receptor (CD200R1) and one or more biomarkers in a biological sample from the patient, the method comprising administering to the patient a CD200 inhibitor in an amount and with a frequency sufficient to reduce the cancer burden in the patient, compared to the cancer burden in the patient prior to treatment with the CD200 inhibitor, wherein the one or more biomarkers are selected from the group consisting of Inducible T-cell COStimulator (ICOS), T Cell Immunoreceptor with Ig and ITIM Domains (TIGIT), Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSP9), Hepatitis A Virus Cellular Receptor 2 (HAVCR2), Programmed Cell Death 1 (PDCD1), Fc Fragment Of IgG Receptor IIa (FCGR2A), Fc Fragment Of IgG Receptor Ia (FCGR1A), Cluster of Differentiation 163 (CD163), and Cluster of Differentiation 14 (CD14).

2. The method of claim 1 , wherein the CD200 inhibitor is selected from the group consisting of a small molecule, a polypeptide, a polypeptide analog, a peptidomimetic, and an aptamer.

3. The method of claim 1 , wherein the CD200 inhibitor is an antibody, or an antigen-binding fragment thereof.

4. The method of claim 3 , wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a humanized antibody, a recombinant antibody, a diabody, a chimerized or chimeric antibody, a monoclonal antibody, a deimmunized antibody, a fully human antibody, a single chain antibody, an F v fragment, an F d fragment, an Fab fragment, an Fab′ fragment, and an F(ab′) 2 fragment.

5. The method of claim 3 , wherein the antibody comprises a heavy chain variable region CDR1 having the sequence set forth in SEQ ID NO: 7, a heavy chain variable region CDR2 having the sequence set forth in SEQ ID NO: 8, a heavy chain variable region CDR3 having the sequence set forth in SEQ ID NO: 9, a light chain variable region CDR1 having the sequence set forth in SEQ ID NO: 4, a light chain variable region CDR2 having the sequence set forth in SEQ ID NO: 5, and a light chain variable region CDR3 having the sequence set forth in SEQ ID NO: 6.

6. The method of claim 3 , wherein the antibody comprises a heavy chain variable region comprising SEQ ID NO: 13 and a light chain variable region comprising SEQ ID NO: 12.

7. The method of claim 3 , wherein the antibody is samalizumab or a variant of samalizumab.

8. The method of claim 3 , wherein the antibody or an antigen-binding fragment thereof, is administered at a dose of about 5 mg/kg to about 50 mg/kg.

9. The method of claim 3 , wherein the antibody is administered at a dose of about 1 mg/kg to about 20 mg/kg.

10. The method of claim 3 , wherein the antibody is administered at a dose of about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, or about 40 mg/kg.

11. The method of claim 1 , wherein expression levels of CD200R1 and the one or more biomarkers are measured by quantitation of protein and/or RNA levels, using at least one of an immunoassay, immunochemistry assay, immunohistochemistry assay, nucleoprobe assay, in situ hybridization, fluorescent RNA probes, RT-PCR, microarray transcription assay, and RNA transcription assay.

12. The method of claim 11 , wherein the immunoassay is an enzyme-linked immunosorbent assay (ELISA) or a radioimmunoassay (MA).

13. The method of claim 1 , wherein the biological sample is at least one of tumor tissue, tumor cells, blood, and a blood fraction.

14. The method of claim 1 , wherein: (i) expression levels of CD200R1 and of one or more biomarkers are measured in two or more types of biological samples; or (ii) expression levels of CD200R1 and of one or more biomarkers are measured in one type of biological sample and levels of a second biomarker are measured in a second type of biological sample.

15. The method of claim 1 , wherein the positive expression of CD200R1 in the biological sample is equal to or greater than expression of CD200R1 in a normal biological sample of the same type.

16. The method of claim 1 , wherein the positive expression of the one more biomarkers in the biological sample is equal to or greater than expression of the one or more biomarkers in a normal biological sample of the same type.

17. The method of claim 1 , further comprising measuring CD200 expression in the biological sample and identifying patients with tumors having elevated expression of CD200, wherein the elevated expression of CD200 in the biological sample is greater than median expression levels of CD200 in normal tissue.

18. The method of claim 1 , wherein the patient has been determined to have elevated expression levels of CD200R1 and at least one biomarker selected from the group consisting of ICOS, TIGIT, TNFRSF9, HAVCR2, PDCD1, FCGR2A, FCGRIA, CD163, and CD14.

19. The method of claim 1 , wherein the patient is an adult and the cancer is selected from the group consisting of diffuse large B cell lymphoma (DLBL), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), glioblastoma (GBM), low grade glioma (LGG), clear cell RCC (KIRC), chromophobe (KICH), papillary cell RCC (KIRP), melanoma (SKCM), ovarian cancer (OV), colon cancer (COAD), rectum cancer (READ), uterine endometrial cancer (UCEC).

20. The method of claim 1 , wherein the patient is a pediatric patient, and the cancer is selected from atypical teratoid rhabdoid tumor (AT/RT), ependymoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, pilocytic astrocytoma, neuroblastoma, and retinoblastoma.

21. The method of claim 19 , wherein the cancer is DLBL, LUAD, or GBM.

Assignees

• Alexion Pharma Inc

Inventors

• Ji Rui-Ru
• Hamilton Mark
• Barr Sharon

Classifications

• G01N33/57557

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/5758 Primary

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• G01N33/575 Primary

  for cancer · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title