Modified J-Chain Antibody Avidity for T-Cell Blockade

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Solution Overview

Problem

Monoclonal IgG antibodies directed against T-cell inhibitory signaling pathways have shown minimal efficacy in clinical settings and are limited by immune-related adverse events due to their therapeutic index, necessitating the development of binding molecules with increased avidity to achieve effective blockade at lower dosages.

Innovation Solution

Modification of the J-chain in IgM, IgA, IgG/IgM, or IgG/IgA antibodies with the introduction of a binding moiety that interacts with T-cell signaling pathways, allowing these antibodies to bind to different antigens while enhancing avidity and specificity, thereby facilitating effective blockade of T-cell inhibitory or stimulatory pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If monoclonal IgG antibodies are used to block T-cell inhibitory signaling pathways, then the therapeutic approach is simple and well-established, but the efficacy is minimal and immune-related adverse events occur due to limited therapeutic index

Engineering Contradiction:

Improveefficacy of T-cell pathway blockadeVSAvoidimmune-related adverse events

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the key parameter of antibody avidity by using IgM or IgA isotypes instead of IgG, and further modifies the J-chain to include additional binding moieties. This increases the valency and avidity of the antibody, enabling effective T-cell pathway blockade at lower dosages and reducing immune-related adverse events

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite antibody structures by fusing multiple functional domains into the J-chain, including binding moieties for T-cell signaling pathway components (such as CD3, CD28, CTLA-4, PD-1) alongside the native immunoglobulin structure. This composite design enables simultaneous engagement of multiple targets to enhance therapeutic efficacy

Inventive Principle:

Principle #40Composite materials

2Reliability

If the dosage of monoclonal IgG antibody is increased to achieve effective blockade, then the therapeutic effect improves, but immune-related adverse events increase

Engineering Contradiction:

Improvetherapeutic effectVSAvoidimmune-related adverse events

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent fundamentally changes the dosage parameter by increasing antibody avidity through IgM/IgA isotype selection and J-chain modification. This allows achieving effective therapeutic blockade at lower dosages, thereby decoupling therapeutic effect from adverse event incidence

Inventive Principle:

Principle #35Parameter changes

3Reliability

If antibody avidity is increased through IgM or IgA isotypes, then potency and therapeutic index improve, but antibody structure and production complexity increase

Engineering Contradiction:

Improvepotency and therapeutic indexVSAvoidantibody structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent makes the J-chain a multi-functional element by incorporating multiple binding moieties that can target different T-cell signaling pathway components. This universal design allows a single antibody construct to engage multiple targets simultaneously, enhancing potency while managing structural complexity through modular domain organization

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS11639389B2Binding molecules with modified J-chain

Publication Date: 2023.05.02 IGM BIOSCIENCES INC

AI summary

The present invention provides binding molecules that include an IgM, IgA, IgG/IgM or IgG/IgA antibody with a modified J-chain that includes a binding moiety that antagonizes a T-cell inhibitory signaling pathway, and their uses.