Humanized Integrin Alpha10 Antibody for Cancer Therapy
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Solution Overview
Problem
Current cancer therapies targeting integrin α10β1 face challenges due to the immunogenicity of mouse antibodies, which limits their clinical use, and the need for antibodies with improved binding affinities and reduced immunogenicity.
Innovation Solution
Development of a humanized integrin alpha10 antibody, specifically binding to the extracellular I-domain of the integrin alpha10 subunit, which inhibits adhesion, proliferation, and migration of cancer cells, and reduces tumor growth and metastasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse antibodies are used to target integrin α10β1 in cancer therapy, then binding affinity and functional blocking are improved, but immunogenicity increases leading to generation of human anti-mouse antibodies
Solution Approach 1:
The patent uses a humanized antibody as an intermediary that bridges the gap between mouse-derived affinity and human compatibility. The antibody framework is humanized to reduce immunogenicity while maintaining the ability to bind integrin α10β1 with high affinity, thus resolving the contradiction between binding effectiveness and immunogenicity.
Solution Approach 2:
The patent applies parameter changes by modifying the antibody sequence parameters (humanization) while preserving the critical binding parameters (affinity and functional blocking). This allows the antibody to maintain cancer therapeutic efficacy while reducing immunogenicity to acceptable levels for clinical use.
2Object-affected harmful factors
If humanized antibodies are developed to reduce immunogenicity, then clinical usability is improved, but binding affinity may be decreased compared to original mouse antibody
Solution Approach 1:
The patent extracts the critical binding determinants from the mouse antibody and transplants them into a humanized framework. By separating the binding function (extracted from mouse sequences) from the immunogenic components (removed in humanization), the patent achieves both low immunogenicity and maintained binding affinity.
Solution Approach 2:
The patent creates a humanized copy of the mouse antibody that replicates the binding characteristics while using human genetic material. This copying approach preserves the functional affinity of the original mouse antibody through careful selection of human sequences that mimic the binding interface, while avoiding the immunogenicity of mouse sequences.
3Reliability
If integrin α10β1 is targeted for cancer therapy, then tumor growth and metastasis are reduced, but the complexity of developing clinically applicable antibodies increases
Solution Approach 1:
The patent segments the antibody development process into manageable components: selecting the target (integrin α10β1), deriving the parent antibody (mouse mAb365), humanizing the sequence, and validating functionality. This segmentation reduces the overall complexity by breaking down the development process into discrete, controllable steps with clear objectives for each phase.
Data Source
AI summary
The present invention relates to a novel integrin alphalO antibody, as well as uses thereof in medicine. 25 humanized antibodies (abs) derived from the known mouse mAb365 (the hybridoma deposited under the accession number DSM ACC2583) are disclosed. The ones which bind specifically the integrin alpha 10 beta 1 were selected. Out of the 25 humanized variants 5 were selected as lead candidates (designated TAR-Ab8, TAR-Ab9, TAR-Abl3, TAR-Abl4 and TAR-Ab23) since these 5 entire antibodies were shown to have improved thermal stability as compared to the chimeric antibody designated TAR-Ab0. There is further functional characterization only of TAR-Ab23 which has higher binding affinity than mAb365.