CD3-Binding Antibody Fragments for Stable T-Cell Targeting

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Solution Overview

Problem

Current bi-specific antibodies, such as Blinatumomab, face challenges with poor half-life in vivo and difficult manufacturing due to stability issues, limiting their effectiveness and manufacturability for targeting T-cells to tumor cells.

Innovation Solution

Development of antibodies or antigen binding fragments with specific VH and VL sequences, connected via an amino acid linker, that bind to CD3, including sequences like GVTFNYYG, TLDGRDGWVAY, and QSYSSGFI, with optional Fc domains for enhanced stability and functionality.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If bi-specific antibodies like Blinatumomab are used to target T-cells to tumor cells, then T-cell recruitment efficacy is improved, but half-life in vivo deteriorates

Engineering Contradiction:

ImproveT-cell recruitment efficacyVSAvoidhalf-life in vivo

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies parameter changes by modifying the antibody format from a single-chain construct to a bispecific antibody with separate heavy and light chains containing specific CDR sequences. This structural parameter change improves both T-cell recruitment efficacy and half-life in vivo compared to previous bi-specific antibody formats.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If bi-specific antibodies like Blinatumomab are used to target T-cells to tumor cells, then T-cell recruitment efficacy is improved, but manufacturability deteriorates

Engineering Contradiction:

ImproveT-cell recruitment efficacyVSAvoidmanufacturability

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the structural parameters of the antibody by defining specific CDR sequences in heavy and light chains, which improves manufacturability while maintaining T-cell recruitment efficacy. The standardized sequence definitions enable more consistent production compared to previous formats.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite antibody structure by combining specific heavy chain variable domains with specific light chain variable domains, each containing defined CDR sequences. This composite approach improves both efficacy and manufacturability by optimizing the interaction between the two chains.

Inventive Principle:

Principle #40Composite materials

3Reliability

If bi-specific antibodies like Blinatumomab are used to target T-cells to tumor cells, then T-cell recruitment efficacy is improved, but stability deteriorates

Engineering Contradiction:

ImproveT-cell recruitment efficacyVSAvoidstability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies parameter changes by specifying exact CDR sequences in both heavy and light chains, which enhances the structural stability of the antibody while maintaining its T-cell recruitment function. The defined sequences reduce variability and improve compositional stability.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12129298B2Compositions including CD3 antigen binding fragments and uses thereof

Publication Date: 2024.10.29 DAIICHI SANKYO CO LTD

AI summary

The present disclosure relates generally to immunoglobulin-related compositions (e.g., antibodies or antigen binding fragments thereof) that can bind to CD3 and uses thereof.