Multispecific polypeptide constructs having constrained CD3 binding and related methods and uses

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Solution Overview

Problem

Existing therapeutic antibodies targeting CD3/TCR pathway do not effectively engage T-cells for antigen-dependent activation and depletion due to systemic binding to peripheral T-cells, limiting their efficacy in therapeutic and diagnostic applications.

Innovation Solution

Multispecific polypeptide constructs with a non-cleavable linker connecting an immunoglobulin Fc region and a CD3-binding region, where the Fc region is positioned N-terminal to the CD3-binding region, ensuring antigen-dependent binding and activation of T-cells by positioning antigen binding domains to tumor-associated antigens.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If therapeutic antibodies directly engage CD3 to activate T-cells, then T-cell activation and cytotoxicity are enhanced, but systemic binding to peripheral T-cells occurs causing off-target effects and reduced therapeutic index

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidsystemic T-cell engagement

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The antibody construct performs preliminary binding to the tumor-associated antigen before engaging CD3. The antigen-binding domains first attach to the TAA on the target cell surface, positioning the CD3-binding regions to subsequently engage CD3 only at the antigen-expressing site, preventing premature or systemic T-cell activation

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The tumor-associated antigen serves as an intermediary that mediates the interaction between the antibody construct and T-cells. The antibody must bind to the TAA first, which then facilitates controlled CD3 engagement, using the antigen as a bridge to localize T-cell activation specifically at the tumor site rather than systemically

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If antibody constructs are designed to bind both CD3 and tumor-associated antigens, then antigen-dependent T-cell activation is achieved, but structural complexity and manufacturing difficulty increase

Engineering Contradiction:

Improveantigen-dependent activationVSAvoidpolypeptide construct structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The antibody construct is segmented into distinct functional modules: antigen-binding domains (which can be variable regions from different antibodies) and CD3-binding regions (anti-CD3 specificities), connected by linkers. This modular segmentation allows independent optimization of each function and simplifies the design and manufacturing process compared to attempting to create a single unified binding interface

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The construct employs universal Fc regions from IgG antibodies that provide standardized effector functions (ADCC, ADCP, CDC) and pharmacokinetic properties. This universal Fc module can be combined with different antigen-binding and CD3-binding specificities, allowing a single platform design to address multiple tumor targets without redesigning the entire construct architecture

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20250361319A1Multispecific polypeptide constructs having constrained CD3 binding and related methods and uses

Publication Date: 2025.11.27 INHIBRX BIOSCIENCES INC

AI summary

The invention relates generally to multispecific polypeptides having constrained CD3 binding. In some embodiments, components of the multispecific polypeptides are connected by a non-cleavable linker. Also provided are methods of making and using these multispecific polypeptides in a variety of therapeutic, diagnostic and prophylactic indications.