Trispecific Binding Protein Architecture for Multi-Antigen Specificity

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Solution Overview

Problem

Existing monoclonal antibody technologies are limited in their ability to simultaneously target multiple antigen targets with high specificity and functionality, particularly in complex diseases such as cancer and inflammatory disorders.

Innovation Solution

Development of trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites, allowing for specific binding to one, two, or three antigen targets, with specific configurations of variable domains and linkers to enhance targeting capabilities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If monoclonal antibody technology is used to target multiple antigen targets, then the scope of therapeutic applications is expanded, but the specificity and functionality to simultaneously target multiple antigens is limited

Engineering Contradiction:

Improveability to target multiple antigen targetsVSAvoidspecificity and functionality

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

a first polypeptide chain has a structure represented by the formula: VL2-L1-VL1-L2-CL and a second polypeptide chain has a structure represented by the formula: VH1-L3-VH2-L4-CH1 and a third polypeptide chain has a structure represented by the formula: VH3-CH1 and a fourth polypeptide chain has a structure represented by the formula: VL3-CL

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If traditional antibody engineering is used to create multispecific antibodies, then the scope of antibody drug development is expanded, but the ability to achieve high specificity and potency against multiple targets is constrained

Engineering Contradiction:

Improvescope of antibody drug developmentVSAvoidspecificity and potency

Core Design Contradiction:

Adaptability or versatilityVSManufacturing precision

Solution Approach 1:

wherein: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Adaptability or versatility

If four polypeptide chains with cross-over orientation are used to form three antigen binding sites, then the targeting capabilities are enhanced, but the structural complexity increases

Engineering Contradiction:

Improvetargeting capabilitiesVSAvoidstructural complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair

Inventive Principle:

Principle #7Nested doll (Nesting)

Data Source

PatentEP4257193B1Trispecific and/or trivalent binding proteins

Publication Date: 2025.12.31 SANOFI SA(FR)

Figure 1A~1B
Figure 1C
Figure 2

AI summary

The disclosure provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. The disclosure also provides methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins.