Monovalent CD47 Binding Proteins That Avoid Hemagglutination
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Solution Overview
Problem
Current cancer therapies targeting the CD47 axis do not effectively inhibit CD47/SIRPα interactions and can induce hemagglutination at high concentrations, necessitating the development of alternative and improved therapeutics.
Innovation Solution
Development of monovalent binding proteins, such as antibodies and antibody fragments, that bind specifically to CD47 with high affinity and induce direct tumor cell killing without hemagglutination, utilizing specific CDR sequences for CD47 recognition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies targeting CD47 are used, then CD47/SIRPα interactions are inhibited, but hemagglutination is induced at high concentrations
Solution Approach 1:
The patent divides the conventional bivalent antibody into monovalent binding proteins (such as scFv fragments or Fab fragments) that contain only a single antigen-binding domain. This segmentation eliminates the second binding site that causes cross-linking of red blood cells, thereby preventing hemagglutination while preserving CD47 binding capability
Solution Approach 2:
The patent extracts only the essential antigen-binding portion (variable regions with CDRs) from the complete antibody molecule, discarding the Fc region and other domains that contribute to bivalency. This extracted monovalent binding domain maintains CD47 recognition without the harmful hemagglutination side effect
2Reliability
If conventional antibodies are used, then CD47 binding is achieved, but direct tumor cell killing is not effectively induced
Solution Approach 1:
The patent modifies the binding protein parameters by engineering specific CDR sequences (VH CDR1: NFGMH, VH CDR2: WINTYTGEPTYTDDFKG, VH CDR3: GDYRYGDS, VL CDR1: RSSQSLVHSNGKTYLH, VL CDR2: RVSNRFS, VL CDR3: SQSTHVPFT) that confer not only high affinity CD47 binding but also the unique capability to induce direct tumor cell killing through a different mechanism than SIRPα blockade
3Quantity of substance
If high concentrations of conventional antibodies are used, then CD47 binding is enhanced, but hemagglutination is induced
Solution Approach 1:
By segmenting the antibody into monovalent fragments, the patent allows use of higher concentrations without hemagglutination, as the monovalent structure prevents cross-linking even at elevated concentrations
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
These binding proteins demonstrate rapid and effective tumor cell killing at low concentrations without inducing hemagglutination, providing a novel therapeutic approach for cancer treatment.
Implementation Method 1
one antigen binding domain that binds to CD47, said antigen binding domain comprising a heavy chain variable region that comprises three complementarity determining regions (CDRs), and a light chain variable region that comprises three CDRs
Implementation Method 2
antibodies of the invention, including humanized antibodies of the invention, have been shown to be capable of binding to CD47 with high affinity and surprisingly also show excellent ability to induce direct killing of tumour cells
Data Source
AI summary
The present invention relates to binding protein or antibody comprising one antigen binding domain that binds to CD47, said antigen binding domain comprising a heavy chain variable region that comprises three complementarity determining regions (CDRs), and a light chain variable region that comprises three CDRs, wherein said antigen binding domain binds to Q19, N45, T120, R121, E122 and G123 within CD47 as defined by SEQ ID NO:19, and wherein said binding protein or antibody binds monovalently to CD47. Binding protein and antibody-based compositions, therapeutic methods and kits are also provided.