Tumor-Activated PSMA-CD3 Antibodies With Protease-Gated T Cell Engagement

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Solution Overview

Problem

Existing T cell engager therapies for treating solid tumors face challenges such as cytokine release syndrome, on-target healthy tissue toxicity, and short half-life, limiting their effectiveness and safety in clinical applications.

Innovation Solution

Development of polypeptide complexes that selectively bind to effector cell antigens and PSMA, incorporating a tumor-specific protease substrate and a half-life extending molecule, which are activated in the tumor microenvironment to reduce toxicity and improve stability and half-life.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cell engager therapies are used to treat solid tumors, then tumor targeting capability is improved, but cytokine release syndrome and healthy tissue toxicity occur

Engineering Contradiction:

Improvetumor targeting capabilityVSAvoidcytokine release syndrome and healthy tissue toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The polypeptide complex is divided into distinct functional modules: a first antigen binding domain specific to effector cells (e.g., T cells), a second antigen binding domain specific to tumor cells, a protease substrate linker, and a half-life extending molecule. This segmentation allows independent optimization of each component's function while reducing off-target effects through controlled activation only in the tumor microenvironment.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

A tumor-specific protease substrate linker acts as an intermediary between the two antigen binding domains. This linker remains intact in circulation, preventing premature activation, but is cleaved by tumor-associated proteases in the tumor microenvironment, thereby activating the T cell engagement function specifically at the tumor site and reducing systemic toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 3:

The invention modifies the pharmacokinetic parameters of the T cell engager by incorporating a half-life extending molecule, which changes the clearance rate and circulation time of the therapeutic. This parameter change allows sustained therapeutic levels while reducing the frequency of dosing and minimizing peak-trough fluctuations that contribute to toxicity.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If T cell engager therapies are administered, then therapeutic effect is improved, but half-life is short

Engineering Contradiction:

Improvetherapeutic effectVSAvoidhalf-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The therapeutic construct is designed as a composite molecule combining multiple functional elements: antigen binding domains, protease substrate linker, and half-life extending moieties such as Fc regions or PEG chains. This composite structure integrates the short-lived T cell engager functionality with long-circulation properties, achieving both effective tumor targeting and extended half-life.

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The polypeptide complex performs multiple functions simultaneously: it binds to effector cells and tumor cells, remains stable in circulation through the half-life extending molecule, and can be activated by tumor-specific proteases. This multi-functionality allows a single therapeutic to address both the need for sustained presence in the body and the need for controlled activation at the target site.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The polypeptide complexes effectively target and engage T cells to treat solid tumors with reduced cytokine release syndrome and healthy tissue toxicity, maintaining therapeutic levels and improving pharmacokinetics.

Implementation Method 1

L1 comprises a linking moiety that connects A1 to P1 and is a substrate for a tumor specific protease

Methodology Applied

Scientific EffectProtease cleavage: Enzyme

Implementation Method 2

P1 comprises a peptide that binds to A1

Methodology Applied

Scientific EffectPeptide-protein binding:

Implementation Method 3

H1 comprises a half-life extending molecule

Methodology Applied

Scientific EffectHalf-life extension:

Implementation Method 4

A2 comprises a second antigen recognizing molecule that binds to prostate-specific membrane antigen (PSMA)

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentUS20260001963A1Compositions and methods related to tumor activated antibodies targeting PSMA and effector cell antigens

Publication Date: 2026.01.01 JANUX THERAPEUTICS INC

AI summary

Provided herein are multispecific antibodies that selectively bind to PSMA and effector cell antigens such as CD3, pharmaceutical compositions thereof, as well as nucleic acids, and methods for making and discovering the same.