CD47 Binding Agents for Selective Tumor Targeting
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Solution Overview
Problem
Current anti-CD47 antibodies face challenges such as broad expression on healthy cells, leading to toxic effects and poor pharmacokinetics, as well as agglutination of red blood cells, which reduces their therapeutic efficacy in targeting tumor cells.
Innovation Solution
Development of CD47 binding agents, including monospecific or bispecific antibodies that compete for binding with CD47, specifically designed to inhibit SIRPα signaling and enhance phagocytic cell function, thereby improving immune surveillance and tumor cell removal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neutralizing antibodies target CD47, then tumor cell phagocytosis is enhanced, but healthy cells are affected leading to toxic effects
Solution Approach 1:
The antibody is engineered to recognize a specific local epitope on CD47 that is preferentially present or conformationally distinct on tumor cells versus healthy cells. This localized recognition allows selective binding to tumor cells while sparing healthy cells expressing CD47, thereby enhancing therapeutic efficacy without causing toxic effects on normal tissues.
Solution Approach 2:
The patent modifies key parameters of the antibody including its affinity constant (Kd), epitope specificity, and binding kinetics to achieve optimal selectivity. By carefully tuning these parameters, the antibody binds with high affinity to tumor cell CD47 while exhibiting reduced binding to healthy cell CD47, thus improving the therapeutic window and reducing off-target toxicity.
2Measurement precision
If neutralizing antibodies target CD47, then tumor cell recognition is improved, but pharmacokinetics are poor due to rapid elimination
Solution Approach 1:
The antibody's pharmacokinetic properties are optimized by modifying parameters such as Fc region structure, half-life extension through FcRn binding, and aggregation state control. These parameter changes extend the circulating half-life of the antibody in vivo, ensuring sustained tumor cell recognition and therapeutic effect without requiring frequent administrations.
Solution Approach 2:
The patent employs antibody fragments or engineered variants with reduced size that can penetrate tumor microenvironments more effectively. These shorter-lived forms are administered at optimized frequencies to maintain therapeutic presence, balancing rapid clearance with sustained anti-tumor activity through repeated dosing schedules.
3Reliability
If CD47 binding agents are used, then immune surveillance is enhanced, but red blood cell agglutination occurs reducing therapeutic effect
Solution Approach 1:
The antibody is designed to bind to a specific local epitope on CD47 that is spatially distinct from the SIRPα binding site on red blood cells. This localized epitope recognition allows the antibody to engage immune surveillance pathways on tumor cells while avoiding cross-linking of RBCs through the SIRPα pathway, thereby preventing agglutination and maintaining therapeutic efficacy.
Solution Approach 2:
The patent introduces an intermediary mechanism where the antibody binds CD47 in a manner that triggers phagocytic recruitment without inducing RBC agglutination. This is achieved by selecting an epitope that, when bound, conformationally prevents SIRPα interaction on RBCs while still allowing immune cell engagement, thus mediating the therapeutic effect without the harmful side effect.
Data Source
AI summary
The present disclosure provides CD47 binding agents (e.g., antibodies, including multispecific antibodies, such as bispecific antibodies) and uses thereof.