Hetero-dimeric CD3/CD38 Antibodies Knob-into-Hole Assembly
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Solution Overview
Problem
Current monoclonal antibodies targeting CD20 are limited in treating multiple myeloma and other cancers due to CD20 expression loss in plasma cells, and existing bispecific antibodies for T cell redirection face challenges in aggregation and efficacy.
Innovation Solution
Development of hetero-dimeric immunoglobulins that bind to both CD3 and CD38, utilizing specific amino acid sequences for improved expression and reduced protein A binding, enabling enhanced T cell redirection and cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional monoclonal antibodies targeting CD20 are used, then B cell malignancies can be treated, but they lose efficacy against multiple myeloma and other cancers where CD20 is not expressed
Solution Approach 1:
The patent creates bispecific antibodies that can bind to two different antigens simultaneously (CD3 on T cells and CD38 on target cells), allowing a single antibody to mediate T cell redirection against multiple cancer types including multiple myeloma, CLL, and other CD38-expressing malignancies, thereby achieving universal applicability across different cancer indications
2Reliability
If existing bispecific antibody formats are used for T cell redirection, then T cell killing can be achieved, but aggregation occurs leading to reduced efficacy and stability
Solution Approach 1:
The patent employs asymmetric heavy chain hetero-dimer formats where the two heavy chains have different structures - one with a knob domain and one with a hole domain - preventing symmetric aggregation and ensuring stable heterodimer formation without homodimer contamination, thereby improving antibody stability and efficacy
Solution Approach 2:
The patent introduces localized structural modifications at specific domains (CH3 domain engineering with knob-into-hole technology) to control assembly specificity, where only the complementary knob and hole regions interact, preventing non-specific aggregation while maintaining functional antigen binding sites
3Duration of action of stationary object
If Fc-based bispecific antibody formats are used, then circulation half-life is extended, but protein A binding is increased complicating purification
Solution Approach 1:
The patent modifies the Fc region parameters by introducing point mutations (e.g., L234A, L235A substitutions) that specifically reduce or eliminate protein A binding while preserving FcRn binding functionality, thereby maintaining extended circulation half-life through neonatal Fc receptor-mediated recycling while enabling simplified purification processes
Data Source
AI summary
The present invention relates to hetero-dimeric immunoglobulins that target both a component of the human CD3 antigen and a component of the human CD38 antigen and methods of making the same. The present invention also relates to antibodies which bind to the human CD38 antigen and derivatives thereof for use as therapeutic or diagnostic reagents and methods of making the same.