ICAM-1 CAR I-Domain Affinity Tuning for Tumor Selectivity
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Solution Overview
Problem
Conventional CARs with high affinity to tumor antigens risk collateral targeting of healthy tissues due to low selectivity, leading to on-target, off-tumor toxicity, limiting the effectiveness of CAR T cell therapy.
Innovation Solution
Development of chimeric antigen receptors (CARs) with human I domains that target ICAM-1, featuring affinities ranging from 1 mM to 1 nM, which minimize systemic toxicity by selectively lysing cells with high ICAM-1 expression while sparing normal cells with lower densities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If CAR molecules with high affinity to tumor antigens are used, then sensitivity to target cells is improved, but selectivity deteriorates leading to on-target off-tumor toxicity
Solution Approach 1:
The patent applies parameter changes by systematically varying the affinity of the I domain to ICAM-1 across a broad range (from micromolar to nanomolar Kd values) through site-directed mutagenesis of specific residues (MIDAS site and adjacent residues). This allows optimization of the balance between sensitivity and selectivity by selecting affinity values that provide sufficient tumor cell recognition while avoiding excessive binding to normal tissues.
Solution Approach 2:
The patent applies local quality by focusing mutations specifically at the ICAM-1 binding interface of the I domain (particularly the MIDAS site and adjacent residues) rather than throughout the entire CAR molecule. This localized modification allows precise tuning of affinity and selectivity properties without affecting other functional domains of the CAR.
2Measurement precision
If CAR molecules with increased sensitivity are engineered, then recognition of tumor cells with low antigen density is improved, but collateral targeting of healthy tissues increases
Solution Approach 1:
The patent resolves this contradiction by establishing an optimal affinity window (micromolar to low nanomolar Kd range) through systematic parameter optimization. Affinity values within this window provide sufficient sensitivity to detect low antigen density on tumor cells while maintaining selectivity against normal tissues through the density-dependent activation mechanism.
Solution Approach 2:
The patent applies dynamics by exploiting the density-dependent nature of CAR activation. The I domain CARs are designed to respond dynamically to varying ICAM-1 densities, with activation thresholds that can discriminate between tumor cells (high density) and normal cells (low density), allowing the same receptor to function differently based on local antigen concentration.
3Ease of manufacture
If conventional single-chain antibody format CARs are used, then ease of manufacture is improved, but therapeutic index deteriorates due to reduced selectivity
Solution Approach 1:
The patent applies parameter changes by modifying the affinity parameter of the I domain while maintaining the conventional single-chain antibody format. This allows optimization of the therapeutic index through affinity tuning without complicating the manufacturing process, as the I domain structure remains compatible with standard CAR construction methods.
Solution Approach 2:
The patent applies composite materials by creating a chimeric structure that combines the I domain (from LFA-1 integrin) with antibody-derived single-chain fragment variable (scFv) or other antigen-sensing elements. This composite approach leverages the natural affinity and selectivity properties of the I domain while maintaining the manufacturability and structural advantages of conventional CAR formats.
Data Source
AI summary
The present invention relates to chimeric antigen receptors (CARs) specific to ICAM-1 comprising I domain of the αL subunit of human lymphocyte function-associated antigen 1 (LFA-1). The invention particularly relates to CARs comprising human I domains having different affinities (1 mM to 1 nM Kd) to ICAM-1. CAR T cells comprising human I domain having a low affinity (1 to 200 μM Kd) to ICAM-1 can avoid targeting healthy tissues with basal ICAM-1 expression while simultaneously exhibiting increased potency and long-term efficacy against tumor tissues with high ICAM-1 expression. The present invention also relates to an adoptive cell therapy method for treating cancer by administering the CAR-T cells comprising human I domain to a subject suffering from cancer, whereby the CAR T cells bind to the cancer cells overexpressing ICAM-1 and kill the cancer cells.