Bispecific CD47-CD38 Antibodies With Tuned Affinity for Lower Toxicity
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Solution Overview
Problem
Current treatments for multiple myeloma, particularly relapsed/refractory cases, lack effective therapeutic options due to the heterogeneity of the disease and inherent therapeutic resistance, necessitating a broader therapeutic window for bispecific antibody-based therapies targeting CD38 and CD47 to enhance efficacy and reduce toxicity.
Innovation Solution
Development of bispecific antibodies that bind to both CD38 and CD47, with varying configurations and affinities, including monoparatopic and biparatopic designs, to enhance therapeutic efficacy and specificity, potentially combined with other agents for improved treatment of multiple myeloma and other cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional single-specific antibodies are used to target CD38 or CD47, then some therapeutic effect is achieved, but the therapeutic window is narrow and toxicity occurs at higher doses
Solution Approach 1:
The patent combines two different antigen-specific binding sites (anti-CD38 and anti-CD47) into a single bispecific antibody molecule. This merging allows the antibody to simultaneously target both CD38 and CD47 on myeloma cells, achieving enhanced therapeutic efficacy while maintaining a broader therapeutic window and reducing toxicity compared to conventional single-specific antibodies.
2Productivity
If high doses of bispecific antibodies are administered to enhance efficacy, then therapeutic effect improves, but toxicity increases
Solution Approach 1:
The patent optimizes the affinity parameters of the binding sites by selecting specific antibody fragments (e.g., anti-CD38 monoclonal antibody fragments with defined affinity, anti-CD47 monoclonal antibody fragments with defined affinity). This parameter optimization allows achieving high therapeutic efficacy at appropriate doses without excessive toxicity, as the balanced affinity configuration enables effective target engagement without oversaturation.
3Strength
If bispecific antibodies with high affinity for both CD38 and CD47 are designed, then binding strength improves, but the therapeutic window narrows due to increased risk of off-target effects
Solution Approach 1:
The patent applies different affinity characteristics to different binding sites within the same bispecific antibody molecule. Specifically, it uses anti-CD38 monoclonal antibody fragments with a defined affinity range and anti-CD47 monoclonal antibody fragments with a defined affinity range. This local quality differentiation allows each binding site to be optimized for its specific target while maintaining overall balance, thereby preserving a broad therapeutic window even with strong binding capabilities.
Data Source
AI summary
Novel bispecific heterodimeric immunoglobulins that target both a component of the human CD47 antigen and human CD38 antigen are provided and in particular those comprising an anti-CD38 heavy chain variable region and a light chain variable region and an anti-CD47 heavy chain variable region and a light chain variable region. The present invention also relates to the use of this 5 novel class of bispecific heterodimeric immunoglobulins to treat autoimmune and proliferative diseases and in particular cancers such as hematologic malignancies and solid tumors.