Protease-Activatable PSMA-CD3 Engagers for Cold Prostate Tumors
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Solution Overview
Problem
There is a long-felt and unmet need for therapeutic interventions targeting prostate-specific membrane antigen (PSMA)-expressing tumors, particularly immunologically 'cold' tumors, which are characterized by low immune cell infiltration and weak neoantigen burden, and current immunotherapies have shown limited success in prostate cancer.
Innovation Solution
Development of antigen-binding molecules, including bispecific T cell engagers (TCEs) that target PSMA and CD3, with protease-cleavable linkers and activatable forms, designed to recruit and activate T cells in a major histocompatibility complex-independent manner, enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitors are used to treat prostate cancer, then immune cell infiltration is increased, but response rates remain low due to immunologically cold tumor microenvironment
Solution Approach 1:
The patent introduces bispecific T cell engagers as intermediary molecules that bridge T cells and PSMA-expressing tumor cells. These engagers bind to both CD3 on T cells and PSMA on tumor cells, forcing immunological interaction and activating T cell-mediated killing in cold tumors where spontaneous immune infiltration is low.
Solution Approach 2:
The patent replaces the passive immune system reliance (which fails in cold tumors) with an active pharmacological system. The bisspecific engagers mechanically force T cell-tumor cell interaction through their dual-binding capability, substituting the need for spontaneous immune infiltration with drug-induced engagement.
2Reliability
If traditional immunotherapies are used, then treatment approach is simple, but therapeutic efficacy is limited in PSMA-expressing tumors
Solution Approach 1:
The patent employs composite molecular structures in the form of bispecific antibodies and T cell engagers that combine multiple functional domains: PSMA-binding arms, CD3-binding arms, and protease-cleavable linkers. This composite design enables simultaneous targeting of tumor cells and activation of T cells through a single molecular entity.
Solution Approach 2:
The patent incorporates dynamic elements including protease-cleavable linkers that allow the engager to transition from an inactive circulating form to an active tumor-site form. The linkers are designed to be stable in circulation but cleaved by proteases in the tumor microenvironment, activating the therapeutic function where needed.
3Reliability
If bisspecific T cell engagers with protease-cleavable linkers are used, then T cell activation is enhanced, but molecular complexity increases
Solution Approach 1:
The patent divides the bisspecific engager into distinct functional segments: a PSMA-binding domain, a protease-cleavable linker, and a CD3-binding domain. This segmentation allows each component to perform its specific function while maintaining overall modularity. The protease-cleavable linker acts as a separable element that can be cleaved to release or activate specific binding domains.
4Reliability
If checkpoint inhibitors are combined with bisspecific T cell engagers, then therapeutic response is improved, but treatment regimen complexity increases
Solution Approach 1:
The patent employs preliminary action through the design of inactive pro-drug forms of the bisspecific engagers that are administered first, followed by activation at the tumor site. Alternatively, the engagers can be administered concurrently with or after checkpoint inhibitors, preparing the tumor microenvironment for enhanced response to the checkpoint inhibitor therapy.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The described molecules enhance T cell-mediated killing of PSMA-expressing cells, potentially improving therapeutic responses to checkpoint inhibitors and addressing the challenges of immunologically cold tumors.
Implementation Method 1
a protease-cleavable release segment positioned between the mask polypeptide and the bisspecific antibody domain such that the mask polypeptide is capable of reducing the binding of the bisspecific antibody domain to CD3 or PSMA, and wherein the protease-cleavable release segment is cleavable by at least one protease that is present in a tumor
Data Source
AI summary
Provided herein are, inter alia, antigen-binding molecules with binding specificity to cluster of differentiation 3 T cell receptor (CD3), antigen-binding molecules with binding specificity to prostate-specific membrane antigen (PSMA), cleavable linker sequences, and protease-activatable bispecific fusion proteins such as protease-activatable T cell engagers, as well as uses and methods of treatment.