Bispecific CD28-PSMA Antibodies for Localized T Cell Costimulation
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Solution Overview
Problem
Current antibody-based therapies for prostate cancer, particularly those targeting Prostate Specific Membrane Antigen (PSMA), face challenges such as toxicity and non-discriminatory activation of immune responses, leading to peripheral toxicity and limited efficacy.
Innovation Solution
Development of heterodimeric anti-CD28 x anti-PSMA antibodies in the 1+1 Fab-scFv-Fc format, which selectively bind to CD28 on T cells and PSMA on tumor cells, enhancing anti-tumor activity while minimizing peripheral toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If agonistic costimulatory receptor antibodies are used to enhance anti-tumor activity, then T cell activation is improved, but peripheral toxicity increases due to non-discriminatory activation of T cells
Solution Approach 1:
The bispecific antibody is engineered with one binding domain for CD28 (costimulatory receptor) and another for a tumor-associated antigen. This dual-specificity enables the antibody to deliver costimulatory signals locally at the tumor site by requiring simultaneous binding to both CD28 on T cells and the tumor antigen, thereby enhancing anti-tumor activity while minimizing peripheral toxicity through spatially restricted T cell activation.
2Reliability
If monospecific full-length antibodies are used for costimulatory receptor agonism, then T cell activation is enhanced, but selectivity between TILs and peripheral T cells is lost
Solution Approach 1:
The bispecific antibody structure requires simultaneous engagement of CD28 on T cells and a tumor-associated antigen to trigger full activation. This dual-binding requirement creates a localized activation signal specifically at the tumor site where both targets are present, thereby enhancing selectivity for tumor-infiltrating lymphocytes over peripheral T cells while maintaining robust T cell activation.
Solution Approach 2:
The bispecific antibody acts as an intermediary that bridges T cells and tumor cells through its dual binding domains. By requiring simultaneous binding to both CD28 on T cells and the tumor antigen, the antibody mediates selective activation only at the tumor site, preventing non-specific activation of peripheral T cells and enhancing therapeutic selectivity.
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 antibodies enhance anti-tumor activity at tumor sites, providing a targeted immune response that complements other therapies like anti-CD3 x anti-PSMA antibodies, reducing peripheral toxicity and improving treatment outcomes for prostate cancer.
Implementation Method 1
Subject anti-CD28 x anti-PSMA antibodies are capable of agonistically binding to CD28 costimulatory molecules on T cells and PSMA on tumor cells
Data Source
AI summary
Provided herein are novel anti-CD28 x anti-PSMA antibodies and methods of using such antibodies for the treatment of PSMA-associated cancers. Subject anti-CD28 x anti-PSMA antibodies are capable of agonistically binding to CD28 costimulatory molecules on T cells and PSMA on tumor cells. Thus, such antibodies selectively enhance anti-tumor activity at tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies (e.g., anti-CD3 x anti-PSMA antibodies) for the treatment of prostate cancers.