Antagonist Antibody Polypeptides for IBD Treatment
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Solution Overview
Problem
Current monoclonal antibodies targeting CD40 often exhibit agonist activity, limiting their effectiveness in treating inflammatory bowel diseases (IBD) due to unwanted T cell activation and immune responses.
Innovation Solution
Development of antibody polypeptides with a variable domain sequence similar to BMS3h-56-269, specifically binding to CD40 without agonist activity, administered in combination with immunosuppressive/immunomodulatory agents to treat IBD, including ulcerative colitis, Crohn's disease, and Behcet's disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies targeting CD40 are used to treat IBD, then CD40 activity is blocked, but agonist activity causes unwanted T cell activation and immune responses
Solution Approach 1:
The patent applies local quality by engineering specific mutations in the antibody polypeptide structure (particularly in the Fc region) to create localized functional changes. These mutations selectively eliminate agonist activity while preserving antagonistic activity, allowing different regions of the antibody to have different functional properties - the variable region maintains CD40 binding while the modified Fc region prevents unwanted immune activation.
Solution Approach 2:
The patent employs parameter changes by modifying specific amino acid residues in the antibody polypeptide sequence (such as changing L234 and L235 to proline in IgG1, or modifying hinge region flexibility). These parameter changes alter the physical and functional properties of the antibody, transforming it from having both agonist and antagonistic activity to having only antagonistic activity, thereby resolving the contradiction.
2Reliability
If CD40 is activated to enhance immune response, then cytokine production and antigen presentation are improved, but autoimmunity and allergic responses are triggered
Solution Approach 1:
The patent applies preliminary anti-action by designing antibody polypeptides that preemptively block CD40 in a controlled manner before pathological activation can occur. The antagonistic antibodies bind to CD40 and prevent ligand-induced activation, thereby preventing both the beneficial immune responses and the harmful autoimmune/allergic responses that would otherwise occur upon CD40 activation.
Data Source
AI summary
A method of treating an inflammatory bowel disease is provided. The method comprises administration of an antibody polypeptide that specifically binds a novel epitope of human CD40. The antibody polypeptides do not exhibit CD40 agonist activity. The antibody polypeptides may be fusions of a domain antibody (dAb) comprising a single VL or VH domain and an Fc domain.