US-12622976-B2 - Targeting CLPTM1L for treatment and prevention of cancer

US12622976B2US 12622976 B2US12622976 B2US 12622976B2US-12622976-B2

Abstract

Provided herein are therapeutic agents having specificity for human CLPTM1L/CRR9 polypeptide, including therapeutic agents comprising one or more CLPTM1L-targeting agents, compositions comprising such therapeutic agents, and methods of using such compositions for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTM1L/CRR9 protein dysfunction (e.g., pathogenic production, modification, or function). In particular, provided herein are fully human monoclonal antibodies against human CLPTM1L/CRR9 protein and methods of using such antibodies for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTM1L/CRR9 protein dysfunction (e.g., pathogenic production, modification, or function).

Inventors

Michael A. James

Assignees

THE MEDICAL COLLEGE OF WISCONSIN, INC.

Dates

Publication Date: 20260512
Application Date: 20241001

Claims (10)

1 . A method for treating a tumor in a subject in need thereof, the method comprising: administering an effective amount of an antibody or antigen binding fragment thereof, to the subject, wherein the antibody comprises (a) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:36, a CDRH2 of SEQ ID NO:37, and a CDRH3 of SEQ ID NO:38; and a light chain variable region comprising a CDRL1 of SEQ ID NO:39, a CDRL2 of SEQ ID NO:40, and a CDRL3 of SEQ ID NO:41; (b) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:42, a CDRH2 of SEQ ID NO:43, and a CDRH3 of SEQ ID NO:44; and a light chain variable region comprising a CDRL1 of SEQ ID NO:45, a CDRL2 of SEQ ID NO:46, and a CDRL3 of SEQ ID NO:47; (c) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:48, a CDRH2 of SEQ ID NO:49, and a CDRH3 of SEQ ID NO:50; and a light chain variable region comprising a CDRL1 of SEQ ID NO:51, a CDRL2 of SEQ ID NO:52, and a CDRL3 of SEQ ID NO:53; (d) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:54, a CDRH2 of SEQ ID NO:55, and a CDRH3 of SEQ ID NO:56; and a light chain variable region comprising a CDRL1 of SEQ ID NO:57, a CDRL2 of SEQ ID NO:58, and a CDRL3 of SEQ ID NO:59; or (e) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:60, a CDRH2 of SEQ ID NO:61, and a CDRH3 of SEQ ID NO:62; and a light chain variable region comprising a CDRL1 of SEQ ID NO:63, a CDRL2 of SEQ ID NO:64, and a CDRL3 of SEQ ID NO:65.
2 . The method of claim 1 , wherein the antibody is a monoclonal antibody.
3 . The method of claim 2 , wherein the monoclonal antibody is a chimeric antibody, human antibody, humanized antibody, recombinant antibody, engineered antibody, conjugated antibody, bispecific monoclonal antibody, or fragment thereof.
4 . The method of claim 1 , wherein the antibody is an immunoconjugate comprising a therapeutic agent selected from a pharmacologic agent, radioisotope, and toxin; and a linker.
5 . The method of claim 1 , wherein the tumor is a solid tumor selected from the group consisting of glioblastoma, sarcoma, carcinoma, and lymphoma.
6 . The method of claim 1 , wherein the tumor is associated with a cancer or preneoplastic lesion selected from the group consisting of lung cancer, pancreatic cancer, prostate cancer, skin cancer, bladder cancer, kidney cancer, ovarian cancer, colon cancer, colorectal cancer, breast cancer, cervical cancer, brain cancer, esophageal cancer, and stomach cancer, or a precancerous lesion thereof.
7 . The method of claim 6 , wherein the tumor is associated with lung cancer or preneoplastic lesion thereof.
8 . The method of claim 1 , wherein the tumor exhibits resistance to a chemotherapeutic agent.
9 . The method of claim 8 , wherein the chemotherapeutic agent is selected from cisplatin, gemcitabine, carboplatin, carmustine (BCNU), methotrexate, fluorouracil (5-FU), goserelin, leuprolide, tamoxifen, docetaxel, paclitaxel, aldesleukin, interleukin-2, etoposide (VP-16), interferon α, tretinoin (ATRA), bleomycin, dactinomycin, daunorubicin, doxorubicin, mitomycin, vinblastine, and vincristine.
10 . The method of claim 1 , wherein the antibody is administered with a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/286,748 filed on Apr. 19, 2021, which is the U.S. National Stage of PCT/US2019/056251 filed on Oct. 15, 2019, which claims the benefit of U.S. Provisional Application No. 62/750,450, filed Oct. 25, 2018, the disclosures of which are hereby incorporated by reference in their entireties for all purposes. SEQUENCE LISTING A Sequence Listing accompanies this application and is submitted as an XML file of the sequence listing named “65005301093.xml” which is 89,698 bytes in size and was created on Sep. 20, 2024. The sequence listing is electronically submitted via Patent Center with the application and is incorporated herein by reference in its entirety. BACKGROUND Cancer is a disease that begins with mutation of oncogenes and tumor suppressor genes. Mutation of these critical genes allows for a cancer cell to evolve and ultimately results in pathogenic replication (a loss of normal regulatory control leading to excessive cell proliferation) of various given types of cells found in the human body. Tumor formation, tumor survival, and cancer metastasis require anchorage-independent growth and protection from genotoxin-induced apoptosis and anoikis, a programmed cell death mechanism associated with detachment of tumor cells from an extracellular substrate. Tumor cells require protection from apoptosis and anoikis to invade surrounding tissue and to undergo metastasis. There remains a need in the art for methods for treating or preventing cancer and, in particular, for methods which slow or curb tumor growth and prevent metastasis. BRIEF SUMMARY OF THE DISCLOSURE To address the deficiencies outlined above, this disclosure provides therapeutic agents having specificity for human CLPTM1L/CRR9 polypeptide. In particular, provided herein are fully human monoclonal antibodies against human CLPTM1L/CRR9 protein and methods of using such antibodies for treating or preventing a cancer, pre-cancerous lesion, or other disease condition associated with CLPTM1L/CRR9 protein dysfunction (e.g., pathogenic production, modification, or function. In a first aspect, the present invention provides an isolated antibody, or an antigen binding fragment thereof capable of binding to human CLPTM1L. The antibody can comprise or consist essentially of (a) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:36, a CDRH2 of SEQ ID NO:37, and a CDRH3 of SEQ ID NO:38; and a light chain variable region comprising a CDRL1 of SEQ ID NO:39, a CDRL2 of SEQ ID NO:40, and a CDRL3 of SEQ ID NO: 41; (b) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:42, a CDRH2 of SEQ ID NO:43, and a CDRH3 of SEQ ID NO:44; and a light chain variable region comprising a CDRL1 of SEQ ID NO:45, a CDRL2 of SEQ ID NO:46, and a CDRL3 of SEQ ID NO:47; (c) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:48, a CDRH2 of SEQ ID NO: 49, and a CDRH3 of SEQ ID NO:50; and a light chain variable region comprising a CDRL1 of SEQ ID NO:51, a CDRL2 of SEQ ID NO:52, and a CDRL3 of SEQ ID NO:53; (d) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:54, a CDRH2 of SEQ ID NO:55, and a CDRH3 of SEQ ID NO:56; and a light chain variable region comprising a CDRL1 of SEQ ID NO: 57, a CDRL2 of SEQ ID NO:58, and a CDRL3 of SEQ ID NO:59; or (e) a heavy chain variable region comprising a CDRH1 of SEQ ID NO:60, a CDRH2 of SEQ ID NO:61, and a CDRH3 of SEQ ID NO:62; and a light chain variable region comprising a CDRL1 of SEQ ID NO: 63, a CDRL2 of SEQ ID NO:64, and a CDRL3 of SEQ ID NO:65. The antibody can be a human antibody comprising or consisting essentially of (i) a light chain comprising SEQ ID NO: 26 or a sequence having at least 85% sequence identity to SEQ ID NO:26, and a heavy chain comprising SEQ ID NO:27 or a sequence having at least 85% sequence identity to SEQ ID NO: 27; (ii) a light chain comprising SEQ ID NO:28 or a sequence having at least 85% sequence identity to SEQ ID NO:28, and a heavy chain comprising SEQ ID NO:29 or a sequence having at least 85% sequence identity to SEQ ID NO:29; (iii) a light chain comprising SEQ ID NO:30 or a sequence having at least 85% sequence identity to SEQ ID NO:30, and a heavy chain comprising SEQ ID NO:31 or a sequence having at least 85% sequence identity to SEQ ID NO:31; (iv) a light chain comprising SEQ ID NO:32 or a sequence having at least 85% sequence identity to SEQ ID NO:32, and a heavy chain comprising SEQ ID NO:33 or a sequence having at least 85% sequence identity to SEQ ID NO:33; or (v) a light chain comprising SEQ ID NO:34 or a sequence having at least 85% sequence identity to SEQ ID NO:34, and a heavy chain comprising SEQ ID NO:35 or a sequence having at least 85% sequence identity to SEQ ID NO:35. The antibody can comprise a variant Fc domain. The antibody can be a monoclonal antibody. The monoclonal antibody can be a chimeric antibody, human antibody, humanized antibody, recombinant an