Antibody Elbow Hinge Mutations for Direct Cell Death Control
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Solution Overview
Problem
Current monoclonal antibodies face challenges in effectively targeting signaling pathways and inducing direct cell death, particularly in cancer therapy, where modulating antigens associated with cell signaling is needed for improved therapeutic potential.
Innovation Solution
Mutations in the elbow hinge region of antibodies, specifically at amino acid positions like Val11, Leu11, and Pro151, alter the induction of direct cell death, and when combined with Fc part mutations, allow for selective modulation of direct cell death and effector function, independent of non-substituted parent antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutations are introduced in the elbow hinge region to alter direct cell death induction, then the ability to induce direct cell death is improved, but the overall antibody structure and stability may be affected
Solution Approach 1:
The patent applies local quality by introducing mutations specifically in the elbow hinge region (positions Val11, Leu11, Pro151) while keeping the rest of the antibody structure intact. This localized modification approach allows alteration of direct cell death induction capability without compromising the overall structural stability of the antibody molecule.
Solution Approach 2:
The patent employs parameter changes by substituting specific amino acid residues (Val11, Leu11, Pro151) with different amino acids to modify the elbow angle and thereby change the orientation of variable domains. This parameter modification enables enhanced direct cell death induction while maintaining antibody structural integrity through controlled physical-chemical parameter changes.
2Reliability
If Fc part mutations are combined with elbow hinge region mutations to selectively modulate effector function, then effector function is improved, but the complexity of antibody engineering increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody into distinct functional regions (elbow hinge region and Fc part) and independently optimizing each region. Mutations in the elbow hinge region control direct cell death induction, while Fc part mutations control effector function, allowing selective modulation of each function separately through modular engineering approaches.
Solution Approach 2:
The patent implements multi-functionality by designing antibodies that can simultaneously perform multiple functions: antigen binding, direct cell death induction through elbow hinge mutations, and effector function modulation through Fc mutations. This enables a single antibody construct to achieve multiple therapeutic effects independently and synergistically.
Data Source
AI summary
The present invention relates to modified antibodies. In particular, the present invention relates to recombinant monoclonal antibodies having altered ability to induce direct cell death and effector function. In addition, the present invention relates to nucleic acid molecules encoding such antibodies, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the antibodies of the invention, and to methods of using these antibodies in treatment of disease.