Anti-CD47 Antibodies With Reduced Red Blood Cell Binding
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Solution Overview
Problem
Tumor cells overexpress CD47, which acts as an 'immune checkpoint' to evade immune surveillance, necessitating the development of therapeutic molecules that can target CD47 without significant toxicity to normal cells.
Innovation Solution
Development of monoclonal antibodies and antibody derivatives with high affinity for CD47, including monospecific and multispecific antibodies, designed to target tumor cells and enhance immune response while minimizing binding to normal cells like red blood cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies target CD47 for immune therapy and cancer treatment, then antitumor efficacy is improved, but toxicity to normal cells increases
Solution Approach 1:
The patent applies local quality by engineering antibodies with differential binding characteristics - the antibodies are designed to bind with high affinity to CD47 on tumor cells while having reduced binding to CD47 on normal cells. This is achieved through specific CDR region sequences that recognize tumor-associated conformational states of CD47, thereby localizing the therapeutic effect to tumor sites and sparing normal tissues from toxicity
Solution Approach 2:
The patent employs parameter changes by modifying the binding affinity parameters of the antibodies. The antibodies exhibit a differential binding profile where the dissociation constant (KD) for tumor cell CD47 is significantly lower (higher affinity) compared to normal cell CD47. This parameter differentiation allows selective targeting - maintaining strong binding to tumors for effective immune activation while reducing binding to normal cells to minimize off-target toxicity
2Reliability
If antibodies bind to CD47 with high affinity, then immune response against tumor cells is enhanced, but binding to normal cells like red blood cells increases
Solution Approach 1:
The antibodies exhibit local quality in their binding properties by recognizing specific conformational states or epitopes of CD47 that are more prevalent or differently configured on tumor cells versus normal cells. The CDR regions are engineered to interact with tumor-associated CD47 features, creating a spatial and functional differentiation in binding that enhances tumor targeting while reducing normal cell interaction
Solution Approach 2:
The patent applies partial action by designing antibodies that achieve sufficient binding affinity for effective tumor targeting without excessive binding that would cause normal cell toxicity. The binding affinity is optimized to a threshold level that is adequate for triggering immune responses against tumors but below the level that causes significant off-target effects on normal cells like red blood cells
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 reduce tumor burden and enhance immune response against tumor cells, reducing off-target effects on normal cells.
Implementation Method 1
isolated monoclonal antibodies and antibody derivatives that bind specifically to CD47 with high affinity
Data Source
AI summary
The present disclosure relates to antibodies and antibody derivatives that bind to CD47 (also known as IAP, MER6 and OA3) and methods of using the same. In certain embodiments, an anti-CD47 antibody or antibody derivative disclosed herein exhibits reduced binding to a red blood cell.