p95HER2-Specific CAR Binding Units for Solid Tumor Targeting
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Solution Overview
Problem
Current antigen binding units for targeting p95HER2 in cancer therapy are not suitable for implementation into chimeric antigen receptors (CARs) due to insufficient affinity and specificity, leading to limited therapeutic efficacy against solid tumors, as they often bind to full-length HER2 and healthy tissues, and fail to sustain activity in vivo.
Innovation Solution
Development of novel antigen binding units with specific affinity for the hyperactive 611-CTF isoform of p95HER2, comprising distinct amino acid sequences that form scFv structures, integrated into CARs with a human CD8α hinge, 4-1BB costimulatory domain, and CD3ζ signaling domain, ensuring targeted binding and sustained activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing antigen binding units are used to target p95HER2, then some binding activity is achieved, but affinity and specificity are insufficient, leading to binding with full-length HER2 and healthy tissues
Solution Approach 1:
The patent applies local quality by designing antigen binding units with highly specific CDR sequences that recognize a localized epitope on the 611-CTF isoform of p95HER2. The CDRs are engineered to bind specifically to the truncated receptor form, differentiating local binding characteristics to achieve high specificity without cross-reacting with full-length HER2 or healthy tissues.
Solution Approach 2:
The patent utilizes parameter changes by modifying the amino acid sequences of the CDRs in the antigen binding units. Specific amino acid changes in the CDR regions enable the binding units to distinguish between p95HER2 isoforms and full-length HER2, thereby changing the binding parameters to achieve high affinity and specificity for the truncated receptor.
2Reliability
If CARs are expressed in T cells, then therapeutic activity is achieved in vitro, but migration to tumor metastases and infiltration of tumor microenvironment are limited
Solution Approach 1:
The patent incorporates feedback mechanisms through costimulatory domains (4-1BB and CD28) in the CAR design. These domains provide positive feedback signals that enhance T cell activation, proliferation, and persistence. The feedback from antigen binding triggers downstream signaling pathways that promote CAR-T cell migration and infiltration into the tumor microenvironment, improving therapeutic efficacy.
Solution Approach 2:
The patent applies dynamics by designing CARs with multiple signaling domains that enable dynamic response to antigen stimulation. The CAR structure includes activation domains, costimulatory domains, and intracellular signaling domains that work together to dynamically regulate T cell behavior, enhancing migration and infiltration capabilities in response to tumor antigen presentation.
3Measurement precision
If CAR-T cells are designed with high affinity for p95HER2, then binding specificity is improved, but sustainability of activity in vivo is insufficient
Solution Approach 1:
The patent ensures continuity of useful action by incorporating multiple costimulatory domains (4-1BB and CD28) that provide sustained signaling feedback. This continuous activation signal maintains CAR-T cell functionality and persistence in the tumor microenvironment over time, preventing exhaustion and ensuring prolonged therapeutic activity against p95HER2-expressing tumors.
Solution Approach 2:
The patent utilizes composite materials by integrating multiple functional domains into a single CAR structure. The CAR combines antigen binding units, hinge regions, transmembrane domains, costimulatory domains, and intracellular signaling domains into a composite receptor molecule. This composite design enables simultaneous achievement of high affinity binding and sustained in vivo activity through coordinated function of all domains.
Data Source
AI summary
The present invention provides a binding molecule which specifically binds p95HER2 comprising the amino acid sequence set forth in SEQ ID NO: 17, comprising a light chain variable domain (VL) and a heavy chain variable domain (VH) which together form an antigen binding unit, wherein the VL comprises three complementarity determining regions (CDRs): CDR1, CDR2 and CDR3, which respectively comprise the amino acid sequences SEQ ID NOs: 1, 2 and 3; and wherein the VH comprises three CDRs; CDR1, CDR2 and CDR3, which respectively comprise the amino acid sequences SEQ ID NOs: 4, 5 and 6.