PSMA-Binding Antibody Format for Low Antigen Shift

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Solution Overview

Problem

Existing bispecific antibodies face challenges such as off-target T cell activation, antigen shift, and low serum half-life, limiting their therapeutic efficacy and safety.

Innovation Solution

Development of a PSMA-binding antibody with specific CDR sequences (SEQ ID NO: 3-8) that minimizes antigen shift and off-target activation, and is formulated in a bispecific format (Fabsc or IgGsc) to enhance serum stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional bisspecific antibodies are used to target tumor cells, then T cell activation and tumor lysis are achieved, but off-target T cell activation and systemic toxicity occur

Engineering Contradiction:

Improvetarget cell restricted T cell activationVSAvoidoff-target T cell activation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by creating Fc-depleted or attenuated bispecific antibodies with modified Fc regions that lose FcR binding capability. This allows the antibody to bind target cells through FcγRs locally at the tumor site without causing system-wide FcR-mediated T cell activation, thus achieving target cell restricted activation while preventing off-target effects.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention extracts the harmful FcR binding function from the antibody molecule by deleting or attenuating the Fc region. This removes the source of off-target T cell activation while preserving the essential targeting and T cell activation functions through the Fv region and FcγR interaction.

Inventive Principle:

Principle #2Taking out (Extraction)

2Object-affected harmful factors

If Fc-depleted bispecific antibodies are constructed to prevent FcR binding, then off-target activation is reduced, but serum half-life is shortened

Engineering Contradiction:

ImproveFcR bindingVSAvoidserum half-life

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of stationary object

Solution Approach 1:

The patent applies parameter changes by modifying the Fc region parameters (amino acid sequences, glycosylation patterns) to simultaneously achieve FcR binding attenuation and extended serum half-life. Specific mutations in the Fc region alter the antibody's interaction with FcRn receptors, enhancing serum stability while maintaining reduced FcR binding.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If existing PSMA binding antibodies like J591 are used, then PSMA-expressing cells are targeted, but significant antigen shift occurs

Engineering Contradiction:

ImprovePSMA targetingVSAvoidantigen shift

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The invention applies parameter changes by identifying and binding to a different epitope on PSMA through engineered CDR sequences. This alternative epitope binding prevents the conformational changes and internalization that cause antigen shift, while maintaining effective PSMA targeting and tumor cell recognition.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250346669A1PSMA binding antibody and uses thereof

Publication Date: 2025.11.13 DEUTES KREBSFORSCHUNGSZENT STIFTUNG DES OFFENTLICHEN RECHTS

AI summary

The present invention provides a novel PSMA binding antibody termed 10B3 and pharmaceutical and diagnostic uses of the antibody 10B3. The PSMA antibody 10B3 does not cross-compete with the state of the art PMSA binding antibody J591 and has a reduced induction of antigen shift compared to J591 and a unique reactivity with squamous cell carcinoma (SCC) cells of different origin.