Affinity-Matured CD22 Antibody Enhances CAR Persistence
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Solution Overview
Problem
Current CAR therapies targeting CD19 for pediatric B-cell acute lymphoblastic leukemia face challenges with relapse due to poor CAR persistence and altered antigen expression, leading to diminished efficacy, particularly with CD22 CAR therapy where relapse occurs more frequently with reduced CD22 expression on leukemia cells.
Innovation Solution
Development of an affinity-matured monoclonal antibody, m971-L7, with significantly improved CD22 binding affinity, which is used in conjunction with chimeric antigen receptors (CARs), immunoconjugates, and other therapeutic agents to enhance CD22 targeting and persistence on leukemia cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy targeting CD22 is used to treat B-cell acute lymphoblastic leukemia, then remission induction rate is improved (70% remission), but relapse rate increases due to poor CAR persistence and altered target antigen expression
Solution Approach 1:
The patent applies parameter changes by modifying the affinity parameter of the antibody component in the CAR construct. The affinity-matured antibody component exhibits significantly improved CD22 binding affinity (from about 2 nM to less than 50 pM), which enhances the stability and persistence of CAR T cells by strengthening the binding interaction between the CAR and its target antigen, thereby addressing the poor CAR persistence issue while maintaining high remission induction rates
2Reliability
If CAR T cell therapy is used to target leukemia cells, then therapeutic efficacy is improved, but relapse occurs due to reduced CD22 expression on leukemia cell surface
Solution Approach 1:
The invention addresses the reduction in CD22 antigen expression by implementing parameter changes in the antibody affinity. The affinity-matured antibody component achieves ultra-high binding affinity (less than 50 pM), which compensates for the diminished antigen availability on leukemia cell surfaces. This enhanced affinity ensures that sufficient binding interactions occur even when CD22 expression is reduced, thereby preventing relapse while maintaining therapeutic efficacy
Solution Approach 2:
The patent applies preliminary action by pre-maturing the antibody affinity before the CAR T cells are deployed against the leukemia. The affinity maturation process is performed in advance to create an antibody component with optimized binding characteristics, ensuring that the CAR T cells are equipped with the necessary high-affinity binding capability before encountering the leukemia cells with reduced antigen expression
Data Source
AI summary
An affinity matured anti-CD22 human monoclonal antibody exhibiting significantly higher affinity (less than 50 pM) compared to the parental antibody (affinity of about 2 nM) is described. The anti-CD22 variant antibody or a fragment thereof, such as a single-chain variable fragment (scFv), can be used as the antigen-binding portion of chimeric antigen receptors (CARs), antibody-drug conjugates (ADCs), immunotoxins or multi-specific antibodies for the treatment of B-cell malignancies.