CD47 Antibodies with Specific CDR Sequences for Selective Tumor Targeting
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Solution Overview
Problem
Existing CD47 antibodies that block the interaction with SIRP alpha cause significant platelet aggregation and hemagglutination, limiting their therapeutic effectiveness in targeting CD47 for cancer treatment.
Innovation Solution
Development of antibodies with specific VH and VL CDR sequences that bind to CD47 without significant platelet aggregation or hemagglutination, inhibiting the CD47-SIRP alpha interaction while promoting phagocytosis of tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing CD47 antibodies are used to block SIRP alpha interaction, then anti-tumor activity is improved, but platelet aggregation and hemagglutination occur causing therapeutic limitation
Solution Approach 1:
The patent applies local quality by engineering specific CDR sequences in the antibody variable regions to create differential binding properties. The VH CDR1 sequence (SEQ ID NO: 9 or 10), VH CDR2 (SEQ ID NO: 11 or 12), VH CDR3 (SEQ ID NO: 13 or 14), VL CDR1 (SEQ ID NO: 15 or 16), VL CDR2 (SEQ ID NO: 17 or 18), and VL CDR3 (SEQ ID NO: 19 or 20) are specifically designed to bind CD47 with high affinity while avoiding cross-reactivity with platelet and RBC CD47 that would cause aggregation. This localized sequence optimization in the antigen-binding regions enables selective targeting of tumor cells without triggering homotypic aggregation of normal cells.
Solution Approach 2:
The patent applies parameter changes by modifying the amino acid sequences of the CDR regions to alter the binding characteristics of the antibody. Specifically, the defined VH and VL CDR sequences are engineered to change the affinity and specificity parameters of CD47 binding, enabling the antibody to distinguish between tumor cell CD47 and normal cell CD47. This sequence parameter optimization allows the antibody to block SIRP alpha interaction on tumor cells while avoiding platelet aggregation and hemagglutination side effects.
2Reliability
If bivalent CD47 binding entities are used, then CD47 blocking capability is enhanced, but homotypic cell aggregation is induced
Solution Approach 1:
The patent applies local quality by designing the CDR regions with specific amino acid sequences that create asymmetric binding properties. The VH CDR1 (SEQ ID NO: 9 or 10), VH CDR2 (SEQ ID NO: 11 or 12), and VH CDR3 (SEQ ID NO: 13 or 14) combined with VL CDR1 (SEQ ID NO: 15 or 16), VL CDR2 (SEQ ID NO: 17 or 18), and VL CDR3 (SEQ ID NO: 19 or 20) are engineered to provide high-affinity binding to tumor cell CD47 while having reduced affinity for platelet and RBC CD47. This localized sequence differentiation enables the bivalent antibody to block CD47-SIRP alpha interaction effectively without causing homotypic aggregation of normal cells.
Solution Approach 2:
The patent applies parameter changes by optimizing the amino acid composition and length of the CDR sequences to fine-tune binding affinity and specificity. The defined VH and VL CDR sequences represent optimized parameters that balance strong CD47 blocking capability with minimal off-target binding. This parameter optimization in the antigen-binding regions allows the bivalent antibody structure to exert therapeutic effect without inducing harmful cell aggregation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies effectively target CD47-expressing cells without causing platelet aggregation or hemagglutination, maintaining the ability to block SIRP alpha interaction and promote phagocytosis, thus enhancing therapeutic efficacy in cancer treatment.
Implementation Method 1
an isolated antibody or antigen binding fragment thereof that specifically binds to human or cyno CD47
Implementation Method 2
Blocking the interaction of CD47 with SIRP alpha is capable of promoting phagocytosis of CD47-expressing cells by macrophages
Data Source
Figure 1A~1B
Figure 2A~2D
Figure 3A~3B
AI summary
The present disclosure relates generally to monoclonal antibodies that specifically bind to CD47, more specifically to CD47 antibodies that do not have significant platelet aggregation activity and do not have significant hemagglutination activity. Methods of generating these antibodies and methods of using these monoclonal antibodies as therapeutics are also provided.