Precursor Tri-Specific Antibody Blocking Components

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Solution Overview

Problem

Current multi-specific antibodies for cancer treatment face challenges such as 'off-target' binding to normal tissues, short half-life, and limited efficacy due to cancer cells' ability to develop compensating signaling pathways, leading to low response rates and marginal survival benefits.

Innovation Solution

Development of precursor tri-specific antibody constructs with regulatable half-life enhancing and blocking components that inhibit toxicity prior to binding, allowing for targeted engagement of cytotoxic cells like T cells and NK cells within the tumor microenvironment, reducing non-specific side effects and enhancing effectiveness.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If multi-specific antibodies are used to engage multiple targets simultaneously, then anti-tumor activity is improved, but off-target binding to normal tissues occurs causing toxicity

Engineering Contradiction:

Improveanti-tumor activityVSAvoidoff-target binding toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The antibody construct is designed with blocking components that prevent cytotoxic cell engagement before the antibody reaches the tumor site. These blocking components are removed or inactivated only after tumor binding occurs, allowing the antibody to selectively activate cytotoxic cells at the tumor location while remaining inert in circulation and on normal tissues.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

Blocking components serve as intermediaries that temporarily prevent the cytotoxic arm from engaging with T cells or NK cells. These intermediaries are strategically placed on the antibody construct and are removed through proteolytic cleavage or conformational changes only after tumor antigen binding, thereby mediating selective activation at the tumor site while preventing off-target effects during circulation.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If multi-specific antibodies are designed to activate cytotoxic cells, then tumor cell destruction is enhanced, but half-life of the antibody is reduced

Engineering Contradiction:

Improvetumor cell destruction efficiencyVSAvoidantibody half-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The antibody construct is divided into functionally distinct modules: a tumor-binding arm that provides target specificity and a cytotoxic arm that recruits T cells or NK cells. This segmentation allows each module to be optimized independently, with the tumor-binding arm ensuring prolonged circulation and the cytotoxic arm providing potent but localized tumor destruction.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Blocking components act as intermediaries that protect the cytotoxic arm from premature activation and reduce clearance by the reticuloendothelial system. These intermediaries are removed only after tumor binding, thereby extending the effective half-life of the antibody in circulation while enabling potent tumor cell destruction upon activation.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If blocking components are added to prevent off-target toxicity, then safety is improved, but device complexity increases

Engineering Contradiction:

Improveoff-target toxicityVSAvoidantibody construct complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The blocking components are integrated into the same antibody construct as the tumor-binding and cytotoxic arms, forming a unified tri-specific molecule. This merging approach consolidates multiple functions (tumor binding, cytotoxic cell recruitment, and self-regulation through blocking) into a single molecular entity, reducing the need for separate administrated components and simplifying the overall treatment regimen.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The antibody construct is designed with multi-functionality, where a single molecule performs tumor targeting, cytotoxic cell recruitment, and self-regulation through blocking components. This universal design allows one antibody construct to accomplish multiple therapeutic goals simultaneously, reducing the need for combination therapies and simplifying the treatment approach despite the increased molecular complexity.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20230312753A1Precursor TRI-specific antibody constructs and methods of use thereof

Publication Date: 2023.10.05 IMMUNORIZON LTD

AI summary

Disclosed herein are precursor tri- specific antibody constructs comprising (i) a first binding domain that binds to a tumor associated antigen, (ii) a second binding domain that binds to a first natural killer (NK) cell surface antigen, and (iii) a third binding domain that binds to a T cell surface antigen or a second NK cell surface antigen. The antibody constructs further comprises regulatory domains that regulate binding to the T cell or NK cell surface antigen. Pharmaceutical compositions comprising the precursor constructs and their uses for treating tumors are also disclosed.