Composite Human Antibodies for PD-L1 Binding
Solution Overview
Problem
Current antibodies targeting PD-L1 often have reduced antigen binding affinities and retain immunogenicity due to murine sequences, limiting their therapeutic effectiveness in humans.
Innovation Solution
Development of novel composite, human monoclonal antibodies that specifically bind to PD-L1 with affinities comparable to murine antibodies, derived entirely from human sequences to minimize immunogenicity and enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If conventional humanization techniques are used to create human antibodies from murine antibodies, then immunogenicity is reduced, but antigen binding affinity is reduced
Solution Approach 1:
The patent creates composite human antibodies by combining CDRs from different human antibody repertoires (e.g., CDR1 from one human antibody, CDR2 from another, CDR3 from a third) to form a composite variable region that binds to PD-L1 with high affinity while being fully human in sequence composition, thereby eliminating murine sequences that cause immunogenicity while maintaining or enhancing binding affinity through optimal CDR combinations
Solution Approach 2:
The patent systematically varies the parameters of antibody sequence composition by selecting and combining CDRs from multiple different human antibodies rather than simply grafting murine CDRs onto a human framework, allowing optimization of both affinity and human compatibility through combinatorial selection of CDR sequences from diverse human sources
2Reliability
If murine antibodies are used to target PD-L1, then antigen binding affinity is maintained, but immunogenicity increases limiting therapeutic effectiveness
Solution Approach 1:
The patent creates human copies of the antigen-binding function by synthesizing human CDR sequences that replicate the binding characteristics of murine CDRs, using human germline V and J gene segments to generate CDRs that are structurally and functionally analogous to murine CDRs but compatible with the human immune system, thereby copying the essential binding function without the immunogenicity of murine sequences
Solution Approach 2:
The patent uses human framework regions and CDRs from human antibodies as intermediaries to transfer and express the antigen-binding function in a human-compatible form, allowing the antibody to bind PD-L1 effectively while being recognized as self by the human immune system, thus mediating between the need for high affinity binding and the need for low immunogenicity
Data Source
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AI summary
The present invention is based, in part, on the identification of novel human anti-PD-1, PD-L1, and PD-L2 antibodies. Accordingly, the invention relates to compositions and methods for diagnosing, prognosing, and treating conditions that would benefit from modulating PD-1, PD-Ll, and/or PD-L2 activity (e.g., persistent infectious diseases, autoimmune diseases, asthma, transplant rejection, inflammatory disorders and tumors) using the novel human anti-PD-1, PD-L1, and PD-L2 antibodies described herein.