De-immunized EpCAM Antibodies Reducing T-cell Activation
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Solution Overview
Problem
Current cancer therapies using antibodies often induce significant immune responses due to the presence of T-cell epitopes, limiting their efficacy and leading to unwanted immune reactions.
Innovation Solution
Development of de-immunized antibodies and immunoconjugates with modified amino acid sequences that lack T-cell epitopes, specifically targeting EpCAM, which are designed to elicit reduced immune responses and effectively bind to cancer cells while minimizing immune activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies are used for cancer therapy, then therapeutic efficacy is achieved, but significant immune responses are induced due to T-cell epitopes
Solution Approach 1:
The patent extracts and removes T-cell epitopes from the antibody sequence while preserving the antigen-binding regions. This is achieved by identifying and eliminating immunogenic peptide sequences that trigger immune responses, thereby reducing harmful immune reactions while maintaining therapeutic efficacy against cancer cells
Solution Approach 2:
The patent modifies the amino acid sequence parameters of the antibody to reduce immunogenicity. By changing specific amino acid residues in T-cell epitope regions while maintaining the overall structure and antigen-binding capability, the antibody achieves reduced immune recognition and response
2Object-generated harmful factors
If de-immunized antibodies with modified amino acid sequences are developed, then immunogenicity is reduced, but binding specificity to cancer cells must be maintained
Solution Approach 1:
The patent segments the antibody structure into distinct functional regions: antigen-binding regions (CDRs) that maintain specificity for EpCAM on cancer cells, and framework regions where T-cell epitopes are modified. This segmentation allows independent optimization of binding specificity and reduced immunogenicity in different parts of the antibody molecule
Solution Approach 2:
The patent applies local modifications to specific amino acid sequences within the antibody framework regions while leaving the antigen-binding CDR regions unchanged. This localized approach to de-immunization preserves the high-affinity binding to cancer cell EpCAM while reducing immune recognition only in the modified framework regions
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AI summary
The present disclosure is related to compositions of antibodies and immunoconjugates that potentially lack T-cell epitopes and elicit reduced immune response. The antibody may be an antibody fragment, such as Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments, multimers, and any combination thereof. In a further embodiment, the antibody may bind to an antigen epithelial cell adhesion molecule (EpCAM). In another embodiment, an immunoconjugate may comprise an antibody attached to an effector molecule, wherein the effector molecule may be a radioisotope, an antineoplastic agent, an immunomodulator, a biological response modifier, lectin, a toxin, a chromophore, a fluorophore, a chemiluminescent compound, an enzyme, a metal ion, and any combination thereof.