EGFR×CD28 Bispecific Antibodies for Tumor-Localized T-Cell Activation
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Solution Overview
Problem
Current cancer treatments using monoclonal antibodies face challenges in overcoming the inhibitory tumor microenvironment, leading to inefficient T-cell activation and tumor cell killing, with single-agent PD-1 blockers often insufficient for durable anti-tumor responses and conventional CD28-activating antibodies causing systemic toxicity.
Innovation Solution
Development of bi-specific antibodies targeting CD28 and Epidermal Growth Factor Receptor (EGFR) in combination with PD-1 blocking antibodies to enhance T-cell activation and promote robust anti-tumor immunity, with CD28 activation limited to the tumor site to avoid systemic toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CD28-activating antibodies are used to enhance T-cell activation, then T-cell activation is improved, but systemic toxicity occurs due to widespread CD28 activation throughout the body
Solution Approach 1:
The patent applies local quality by designing a bispecific antibody where one arm binds CD28 on T-cells and the other arm binds EGFR specifically on tumor cells. This ensures that CD28 activation occurs only at the tumor site where both CD28+ T-cells and EGFR+ tumor cells are present, rather than systemically throughout the body. The localized activation at the tumor microenvironment provides the desired T-cell activation while avoiding widespread systemic toxicity.
Solution Approach 2:
The bispecific antibody acts as an intermediary molecule that bridges the T-cell (via CD28 binding) and the tumor cell (via EGFR binding). This intermediary structure enables controlled, localized interaction between immune cells and tumor cells only at the tumor site, mediating the activation signal precisely where needed without causing systemic effects.
2Reliability
If single-agent PD-1 blocking antibodies are used to release the break on T-cell activation, then T-cell activation is partially improved, but durable anti-tumor responses are insufficient
Solution Approach 1:
The patent merges two therapeutic mechanisms into a single bispecific antibody molecule: PD-1 blockade (to release the brake on T-cell activation) and CD28 agonism (to provide co-stimulatory signal 2). By combining these two functions in one agent, the therapy achieves both immediate T-cell activation relief and sustained co-stimulatory signaling, resulting in more durable anti-tumor responses compared to single-agent PD-1 blockade.
3Measurement precision
If monoclonal antibodies are used to target cancer, then tumor cell recognition is improved, but the inhibitory tumor microenvironment prevents efficient T-cell activation and tumor cell killing
Solution Approach 1:
The bispecific antibody serves as an intermediary that physically bridges the T-cell and tumor cell at the interface of the tumor microenvironment. By simultaneously binding CD28 on the T-cell and EGFR on the tumor cell, it creates a stable immunological synapse that overcomes the inhibitory effects of the tumor microenvironment, enabling efficient T-cell activation and tumor cell killing despite the challenging environment.
Data Source
AI summary
The present invention provides multispecific antibodies that bind to EGFR and CD28 (EGFR×CD28) as well as anti-EGFR antibodies. Such antibodies may be combined with a further therapeutic agent such as an anti-PD1 antibody. Methods for treating cancers (e.g., EGFR-expressing cancer) by administering the antibodies (e.g., and combinations thereof with anti-PD1) are also provided. The EGFR×CD28 antibodies of the present invention embody a tumor-targeted immunotherapeutic modality combined with PD-1 inhibition. These bispecific antibodies bind a tumor-specific antigen (TSA) (EGFR) with one arm and the co-stimulatory receptor, CD28, on T-cells with the other arm. Combination therapy with PD-1 inhibitors specifically potentiated intra-tumoral T cell activation, promoting an effector memory-like T cell phenotype without systemic cytokine secretion in a variety of syngeneic and human tumor xenograft models. Combining this class of CD28-co-stimulatory bispecific antibodies with the clinically validated anti-PD-1 treatment provides a well-tolerated antibody therapy with markedly enhanced anti-tumor efficacy.