SIRP-α Antibody Variants for Polymorphic CD47 Modulation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The SIRP-α-CD47 interaction is crucial for immune regulation but is exploited by cancers to evade immune surveillance, and existing antibodies lack specificity and cross-reactivity across human populations, necessitating the development of antibodies with diverse binding specificities and effects on CD47-SIRP-α binding.

Innovation Solution

Development of isolated antibodies with specific VH and VL domains that bind to human, monkey, and murine SIRP-α polypeptides, including variants, and can modulate their interaction with CD47, potentially blocking or enhancing phagocytosis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing antibodies are used to target SIRP-α, then the SIRP-α-CD47 interaction can be modulated, but the antibodies lack specificity and cross-reactivity across human populations due to SIRP-α polymorphism

Engineering Contradiction:

Improvebinding specificityVSAvoidcross-reactivity across populations

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops multiple antibody variants with different binding specificities to cover the polymorphic nature of SIRP-α across human populations. By creating a panel of antibodies that can bind to different SIRP-α variants, the solution achieves universal applicability across diverse genetic backgrounds while maintaining reliable binding to the target protein.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent systematically varies antibody parameters including binding affinity, epitope recognition, and structural characteristics to create antibodies with optimized properties. This includes generating antibodies with different kinetic profiles and binding modes to account for SIRP-α polymorphism, thereby achieving both specificity and broad cross-reactivity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If antibodies block the SIRP-α-CD47 interaction to prevent tumor evasion, then immune surveillance can be enhanced, but the complex polymorphic nature of SIRP-α makes it difficult to identify antibodies with effective binding specificities

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidcomplexity of antibody identification

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex task of identifying effective antibodies into systematic steps including high-throughput screening, affinity maturation, and functional characterization. This breakdown of the identification process into manageable stages reduces complexity while maintaining the ability to discover antibodies with reliable therapeutic effectiveness against polymorphic SIRP-α targets.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs intermediary tools and methods such as phage display libraries, yeast display systems, and computational modeling to facilitate the identification of effective antibodies. These intermediary technologies serve as bridges between the complex polymorphic target and the antibody discovery process, simplifying the identification of therapeutically effective binders.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If CD47 is highly expressed by cancers to evade immune surveillance, then tumor survival is enhanced, but blocking this interaction requires antibodies with precise binding specificities that existing methods cannot provide

Engineering Contradiction:

Improvetumor immune evasionVSAvoidantibody binding specificity

Core Design Contradiction:

Object-affected harmful factorsVSManufacturing precision

Solution Approach 1:

The patent performs preliminary actions in the antibody development process including pre-screening for specificity, pre-optimization of binding characteristics, and pre-characterization of polymorphism recognition. These preliminary steps ensure that antibodies are prepared with the precise binding specificities needed to effectively block the CD47-SIRP-α interaction in tumor contexts before clinical application.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent replaces traditional mechanical antibody selection methods with advanced technologies such as phage display, ribosome display, and computational design algorithms. These substituted approaches enable more precise control over antibody binding specificities and facilitate the identification of antibodies that can precisely target the CD47-SIRP-α interaction in cancer cells.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentEP4119580B1Antibodies against signal-regulatory protein alpha and methods of use

Publication Date: 2025.11.05 ALX ONCOLOGY INC

Figure 1A
Figure 1B
Figure 1C

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.