Anti-AXL Antibodies With Non-Competing Gas6 Binding

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Solution Overview

Problem

Existing anti-AXL antibodies do not effectively inhibit AXL activity in cancer cells and often compete with the ligand Gas6 for binding, limiting their therapeutic efficacy.

Innovation Solution

Development of anti-AXL antibodies that do not compete with Gas6 for binding and are designed to specifically target AXL, allowing for the creation of bispecific antibodies and immunoconjugates with therapeutic moieties for cancer treatment.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing anti-AXL antibodies are used to target AXL, then AXL binding is achieved, but Gas6 binding is blocked and therapeutic efficacy is limited

Engineering Contradiction:

ImproveAXL binding capabilityVSAvoidGas6 binding competition

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The antibody is designed to bind to a specific epitope on the AXL extracellular domain that is spatially separated from the Gas6 binding site. This segmentation of binding sites allows the antibody to attach to AXL without interfering with Gas6 ligand binding, thereby maintaining AXL signaling function while achieving therapeutic inhibition through alternative mechanisms such as receptor internalization or dimerization prevention.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The antibody exhibits localized binding specificity to a particular region of the AXL extracellular domain (such as the Ig-like domains or FNIII repeats) that does not overlap with the Gas6 binding interface. This local quality differentiation enables selective AXL targeting while preserving the ligand binding capability at the Gas6 site, resolving the competition issue.

Inventive Principle:

Principle #3Local quality

2Reliability

If anti-AXL antibodies are designed to block Gas6 binding, then AXL activation is inhibited, but tumor growth inhibition is reduced due to loss of natural regulation

Engineering Contradiction:

ImproveAXL activity inhibitionVSAvoidtumor growth inhibition efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The antibody acts as an intermediary that binds to AXL and induces alternative inhibition mechanisms such as receptor internalization, degradation, or prevention of pathological dimerization, rather than directly blocking Gas6 binding. This intermediary approach allows AXL to maintain its natural ligand binding capability while still achieving therapeutic inhibition through the antibody-mediated mechanisms, thereby improving tumor growth inhibition efficiency.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If conventional anti-AXL antibodies are used, then AXL expression is targeted, but anti-tumor and anti-metastatic activity is insufficient

Engineering Contradiction:

ImproveAXL targeting capabilityVSAvoidanti-tumor activity

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The antibody is designed to induce dynamic changes in AXL receptor behavior, including time-dependent internalization, trafficking to endosomes, and potential degradation pathways. This dynamic mechanism goes beyond static blocking and creates progressive, sustained inhibition of AXL signaling that enhances anti-tumor and anti-metastatic activity while maintaining targeted specificity.

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS12589150B2Antibodies binding AXL

Publication Date: 2026.03.31 GENMAB AS

AI summary

The present invention relates to anti-AXL antibodies, immunoconjugates, compositions and method of treatment of cancer with such anti-AXL antibodies, immunoconjugates, or compositions.