CADAR targeting ADA-producing B cells in anti-TNF therapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The development of anti-drug antibodies (ADAs) against therapeutic anti-TNF-alpha monoclonal antibodies interferes with their efficacy and leads to adverse events, such as enhanced clearance and reduced clinical response, in treating conditions like rheumatoid arthritis and inflammatory bowel disease, with current strategies failing to fully mitigate immunogenicity.
Innovation Solution
A chimeric anti-drug antibody receptor (CADAR) is designed, comprising an extracellular domain with an immunogenic fragment of a therapeutic anti-TNF-alpha monoclonal antibody, a transmembrane domain, and an intracellular signaling domain, which targets and induces killing of B cells producing ADAs, thereby enhancing treatment response and reducing adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic anti-TNF-alpha monoclonal antibodies are used to treat autoimmune diseases, then clinical efficacy is improved, but anti-drug antibodies (ADAs) are formed that interfere with therapy outcomes
Solution Approach 1:
The patent uses the immunogenic fragment (which causes ADA formation) as the basis for creating a therapeutic cell that targets and eliminates ADA-producing B cells. The harmful immunogenicity is converted into a beneficial targeting mechanism where the same fragment that triggers ADAs is used to identify and destroy the cells producing those ADAs
Solution Approach 2:
The patent introduces an intermediary therapeutic cell (such as a CAR-T cell or similar engineered cell) that mediates between the anti-TNF-alpha antibody and the ADA-producing B cells. This intermediary cell expresses a chimeric antigen receptor that specifically recognizes and eliminates the problematic B cells while preserving the therapeutic antibody's function
2Quantity of substance
If ADAs are formed against therapeutic antibodies, then clearance of therapeutic antibodies is enhanced, but treatment duration and efficacy are reduced
Solution Approach 1:
The patent employs preliminary action by using the immunogenic fragment to pre-program therapeutic cells that will proactively seek out and eliminate ADA-producing B cells before they can significantly clear the therapeutic antibody and compromise treatment efficacy. This preventive approach maintains therapeutic antibody levels throughout the treatment duration
3Object-generated harmful factors
If chimeric, humanized and fully human antibodies are developed to reduce immunogenicity, then ADAs are reduced, but immunogenicity is not fully abolished
Solution Approach 1:
The patent extracts the specific immunogenic fragment responsible for ADA formation from the therapeutic antibody and uses it as a targeting element on therapeutic cells. This extraction approach allows selective elimination of ADA-producing B cells without requiring complete humanization of the therapeutic antibody, thereby fully abolishing the ADA problem while maintaining the antibody's therapeutic function
Data Source
AI summary
Provided a chimeric anti-drug antibody receptor (CADAR) specific for anti-drug-antibody-based B cell receptor (BCR), the anti-drug antibody is induced by a therapeutic anti-TNF-alpha monoclonal antibody. Also provided compositions comprising the CADAR, polynucleotides encoding the CADAR, vectors comprising a polynucleotide encoding the CADAR, engineered cells comprising the CADAR, and method using the same.