PD-1 Antibodies with Optimized CDRs for High-Affinity Binding
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Solution Overview
Problem
There is a need for alternative antibodies that bind human PD-1 with high affinity and effectively block its interaction with PD-L1 and PD-L2, as existing antibodies like nivolumab and pembrolizumab have limitations in terms of affinity and efficacy in cancer treatment.
Innovation Solution
Development of antibodies with specific light and heavy chain complementarity determining regions (CDRs) that provide higher affinity and enhanced alloreactivity, including specific amino acid sequences for the light chain (LCDR1, LCDR2, LCDR3) and heavy chain (HCDR1, HCDR2, HCDR3) regions, which enhance binding to human PD-1 and block its interaction with PD-L1 and PD-L2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibodies like nivolumab and pembrolizumab are used to bind human PD-1, then PD-1 interaction with PD-L1 and PD-L2 is inhibited, but the affinity and blocking efficacy are limited
Solution Approach 1:
The patent applies local quality by optimizing specific regions of the antibody structure (CDR regions) to achieve high affinity binding to PD-1. The antibody xd-16 contains specific CDR sequences (LCDR1: RASQGISSWLA, LCDR2: SAASSLQS, LCDR3: QQANHLPFT, HCDR1: KASGGTFSSTAIS, HCDR2: GIWPSFGTANYAQKFQG, HCDR3: ARAEYSSTGTFDY) that are locally tailored to maximize binding effectiveness while maintaining overall antibody functionality.
Solution Approach 2:
The patent employs parameter changes by modifying the amino acid sequences in the CDR regions of the antibody to achieve higher affinity binding. The specific parameter optimization includes the length and composition of CDR loops, the distribution of charged and hydrophobic residues, and the spatial arrangement of complementarity determining regions to enhance binding kinetics and blocking efficacy against PD-1/PD-L1 and PD-1/PD-L2 interactions.
2Reliability
If antibodies with higher affinity are developed to bind human PD-1, then blocking efficacy is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody into distinct functional modules: variable regions (VH and VL) containing CDRs for antigen binding, and constant regions (CH and CL) for effector functions. This modular structure allows independent optimization of binding affinity in the variable regions while maintaining standardized constant regions that facilitate manufacturing and clinical use. The antibody xd-16 is constructed with clearly defined segments that can be produced using standard recombinant DNA technology.
Solution Approach 2:
The patent uses copying by utilizing germline-derived constant region sequences that are already optimized for human protein expression and stability. The constant regions of antibody xd-16 are copied from well-characterized human immunoglobulin sequences, which simplifies manufacturing processes and ensures compatibility with existing antibody production platforms and regulatory requirements.
Data Source
AI summary
The present invention provides antibodies that bind human programmed cell death 1 (PD-1), and may be useful for treating cancer alone and in combination with chemotherapy and other cancer therapeutics.