SIRP-Alpha Antibodies for Cross-Variant CD47 Blocking
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Solution Overview
Problem
The SIRP-α-CD47 interaction is critical for immune regulation and tumorigenesis, but its polymorphic nature and expression in cancers complicate the development of antibodies that effectively modulate this interaction across human populations and animal models, necessitating the identification of antibodies with diverse binding specificities and effects on CD47-SIRP-α binding.
Innovation Solution
Development of isolated antibodies that bind specifically to the extracellular D1 domain of human SIRP-α polypeptides, including variants v1 and v2, as well as monkey and murine SIRP-α polypeptides, with the ability to modulate SIRP-α signaling and enhance phagocytosis or block the SIRP-α interaction with CD47.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibodies are developed to block SIRP-α-CD47 interaction, then immune regulation and phagocytosis are enhanced, but the polymorphic nature of SIRP-α across human populations and animal models reduces binding effectiveness
Solution Approach 1:
The patent develops antibodies that can bind to multiple SIRP-α variants (human v1, v2, and animal models) through a universal binding mechanism. The antibodies are designed to recognize conserved epitopes across polymorphic sequences, enabling a single antibody to function effectively across diverse human populations and preclinical animal models, thereby resolving the contradiction between binding effectiveness and cross-reactivity.
Solution Approach 2:
The invention focuses on targeting specific local regions (conserved epitopes) within the SIRP-α protein structure that remain unchanged across polymorphic variants. By concentrating binding affinity on these invariant local regions rather than attempting to bind the entire variable sequence, the antibodies achieve both high binding effectiveness and broad cross-reactivity across different SIRP-α variants.
2Reliability
If antibodies target the SIRP-α-CD47 interaction, then tumor immune surveillance is enhanced, but the high expression of CD47 in cancers allows tumors to evade immune detection
Solution Approach 1:
The antibodies are designed to preemptively block the SIRP-α-CD47 interaction before tumors can establish immune evasion. By preventing the binding of CD47 to SIRP-α on macrophages and other phagocytic cells, the antibodies eliminate the 'don't eat me' signal that tumors exploit, thereby enhancing immune surveillance effectiveness and counteracting the tumor evasion mechanism.
Solution Approach 2:
The invention converts the harmful effect of CD47-mediated immune evasion into a beneficial therapeutic effect. By targeting and blocking the SIRP-α-CD47 interaction that tumors exploit for protection, the antibodies transform this protective mechanism into a vulnerability that can be exploited for cancer therapy, enhancing phagocytosis of tumor cells.
Data Source
AI summary
Provided herein, inter alia, are isolated antibodies that bind an extracellular domain of a human SIRP-α v1 polypeptide (e.g., the D1 domain), an extracellular domain of a human SIRP-α v2 polypeptide, or both. In some embodiments, the antibodies also bind an extracellular domain of a monkey SIRP-α polypeptide, an extracellular domain of a mouse SIRP-α polypeptide, an extracellular domain of a human SIRP-β polypeptide, and/or an extracellular domain of a human SIRP-γ polypeptide. In some embodiments, the antibodies block or do not binding between an extracellular domain of a human SIRP-α polypeptide and an IgSF domain of a human CD47 polypeptide, while in some embodiments, the antibodies reduce the affinity of a human SIRP-α polypeptide for binding an IgSF domain of a human CD47 polypeptide. Further provided herein are methods, polynucleotides, vectors, and host cells related thereto.