Humanized CD19 Antibodies With Tuned Affinity and Effector Function
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Solution Overview
Problem
Existing antibodies against human CD19 have limitations in effectively targeting and modulating B-cell activity, particularly in treating autoimmune diseases, rheumatoid arthritis, lupus, psoriasis, bone diseases, and B-cell malignancies, due to suboptimal affinity and effector function.
Innovation Solution
Development of humanized anti-human CD19 antibodies with specific amino acid sequences in hypervariable regions, optimized for enhanced binding and effector functions, including mutations to improve affinity and reduce Fc receptor binding, enabling targeted B-cell depletion and modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing antibodies against human CD19 are used, then B-cell targeting is achieved, but therapeutic efficacy is suboptimal due to insufficient affinity and effector function
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the antibody sequence (e.g., mutating Serine at position 27e to Proline in HVR-L1, and Asparagine at position 64 to Glutamine in HVR-H2) to optimize deamidation resistance and enhance binding affinity to CD19, thereby improving therapeutic efficacy while maintaining stability
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific hotspots (HVR-L1 position 27e and HVR-H2 position 64) rather than global modifications, locally improving deamidation resistance and binding affinity without altering the overall antibody structure or function
2Reliability
If antibodies with increased FcγRIIIA affinity are used, then effector function is enhanced, but off-target effects increase
Solution Approach 1:
The patent applies parameter changes by modifying Fc region amino acid residues (such as E233A, E235A, E239A mutations in IgG1 Fc region) to reduce binding affinity to FcγRIIIA, thereby decreasing off-target ADCC effects while preserving on-target B-cell depletion through complement-dependent cytotoxicity and other mechanisms
Data Source
AI summary
Herein is reported an antibody that specifically binds to human CD19, wherein the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 03, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 05, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 20 or 28, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 07, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 08, as well as methods of using the same.