JP-7855148-B2 - Compositions targeting prostate-specific membrane antigen (PSMA), and methods for preparing and using the same.

Inventors

• ドゥブロフスカヤ，ヴィクトーリヤ
• ジョハンセン，エリック
• リウ，ルーカス
• マッキャン，ダラ
• シュレンベルガー，ヴォルカー
• トー，ミルトン

Assignees

• アムニクス ファーマシューティカルズ， インコーポレイテッド

Dates

Publication Date

20260507

Application Date

20240209

Priority Date

20230210

Claims (8)

1. A polypeptide containing the amino acid sequence of SEQ ID NO: 1000.
2. The polypeptide according to claim 1, comprising the amino acid sequence of SEQ ID NO: 1000.
3. A pharmaceutical composition comprising the polypeptide described in claim 1 and one or more pharmaceutically acceptable excipients.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is for treating cancer, and the cancer is characterized by the expression of prostate-specific membrane antigen (PSMA).
5. The pharmaceutical composition according to claim 4, wherein the cancer is prostate cancer.
6. A polynucleotide encoding the polypeptide described in claim 1.
7. A vector comprising a polynucleotide according to claim 6 and a regulatory sequence operably linked to the polynucleotide.
8. A host cell comprising the vector described in claim 7.

Description

(Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63/444,839, filed on 10 February 2023, and U.S. Provisional Patent Application No. 63/499,031, filed on 28 April 2023, the entire contents of which are incorporated herein by reference. Prostate cancer is the second most common cancer in men, and it is estimated that one in nine men in the United States will develop it at some point in their lives. Treatment with radiation, radical prostatectomy, or active surveillance for localized disease (Gleason score less than 6, PSA less than 10 ng/ml) is successful in controlling the disease in its early stages; however, recurrence occurs in 20–50% of men. Patients whose cancer continues to progress despite first-line androgen deprivation therapy (ADT) develop castration-resistant prostate cancer (CRPC), which often metastasizes to the bones, brain, liver, and lungs (metastatic castration-resistant prostate cancer, mCRPC). While chemotherapy such as docetaxel and cabazitaxel has shown improved survival in this population, there is currently no treatment for mCRPC. Prostate-specific membrane antigen (PSMA; also known as folate hydrolase 1 and FOLH1) is an endogenous cell surface membrane protein that is frequently overexpressed in prostate cancer and is often associated with androgen-independent prostate cancer and secondary metastatic lesions. PSMA is also expressed in neovascularization in bladder, kidney, stomach, and colorectal cancers. Immunotherapy has shown mixed successes, including in relation to prostate cancer. While the first cell-based immunotherapy, Cipleucel T (PROVENGE®), was approved for mCRPC in 2010, checkpoint blockade targeting the immunosuppressive receptors PD-1 and CTLA-4 has shown little reduction in response rates in prostate cancer compared to other solid tumor malignancies. This may be due to the immunologically "cold" tumor microenvironment of primary prostate cancer tumors, characterized by low immune cell infiltration and a weak neoantigen load, which has been shown to be necessary for a response to checkpoint blockade inhibitors. There has been a long-standing, unmet need for therapeutic interventions for PSMA-expressing tumors, including immunologically cold tumors. This disclosure provides, in particular, antigen-binding molecules with binding specificity to PSMA, antigen-binding molecules with binding specificity to CD3, and bispecific antigen-binding molecules that bind to both PSMA and CD3, for use in therapeutic settings where specific targeting of PSMA-expressing cells and T-cell-mediated killing are desired. The embodiments disclosed herein address a long-standing unmet need for PSMA-targeted cancer therapies, including T-cell engagers (TCEs) with increased therapeutic index. The embodiments of this disclosure also address a long-standing, yet unmet, need for therapeutic intervention for immunologically cold tumors expressing PSMA, such as solid tumors. Also included are, for example, protease-cleavable linkers, barcode fragments, antibody domain linkers, and activatable TCEs (including those that do not bind to PSMA). Also included are fusion proteins, such as non-TCE fusion proteins, that target PSMA, CD3, and/or include the linkers and other components provided herein. Certain embodiments of this disclosure include compounds, compositions, and methods for increasing the therapeutic response of a target to checkpoint inhibitors (e.g., PD-1 or CTLA-4 inhibitors such as anti-PD1 antibodies or anti-CTLA4 antibodies). In some embodiments, the compounds provided herein recruit and activate effector T cells in a major histocompatibility complex-independent manner via CD3 engagement on T cells. In some embodiments, the compounds are bispecific TCEs administered in an inactive form and activated at and/or within the tumor site. In some embodiments, the bispecific TCEs are administered before initiating checkpoint inhibitor therapy, concurrently with checkpoint inhibitor therapy, or after discontinuing checkpoint inhibitor therapy. Certain aspects of this disclosure relate to a chimeric polypeptide comprising a bispecific antibody domain, wherein the bispecific antibody domain comprises a first antigen-binding domain that specifically binds to prostate-specific membrane antigen (PSMA) and a second antigen-binding domain that binds to cluster of differentiation 3 (CD3), wherein the first antigen-binding domain is VHH or the second antigen-binding domain is Fab or scFV, and the chimeric polypeptide further comprises a mask polypeptide, which is conjugated to the bispecific antibody domain via a linker containing a protease-cleavable release segment located between the mask polypeptide and the bispecific antibody domain, thereby enabling the mask polypeptide to reduce the binding of the bispecific antibody domain to CD3 or PSMA, and the protease-cleavable release segment is cleavable by at least one protease present in the