Human Vh3 Variable Heavy-Only Libraries for Lower Immunogenicity

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Solution Overview

Problem

Existing single domain antibodies derived from camel and llama sources can induce immunogenic effects due to their non-human sequences, limiting their efficacy in diagnostic and therapeutic applications.

Innovation Solution

Development of a VHO library based on human Vh3 family domains, which are homologous to camelid VHHs, allowing for the creation of stable and selective binding moieties for therapeutic and diagnostic use, utilizing M13 bacteriophage display technology to generate and screen diverse VHO domains.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If camelid VHH or single domain antibodies are used, then binding stability and thermal stability are improved, but immunogenicity increases due to non-human sequences

Engineering Contradiction:

Improvebinding stabilityVSAvoidimmunogenicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the species origin parameter of the antibody variable domain from camelid (non-human) to human Vh3 family, thereby reducing immunogenicity while maintaining the single-domain structural stability and binding capabilities through homologous sequence design

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If human Vh3 family domains are used, then immunogenicity is reduced, but library diversity and binding affinity may be limited compared to camelid sources

Engineering Contradiction:

ImproveimmunogenicityVSAvoidbinding affinity

Core Design Contradiction:

Object-affected harmful factorsVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by introducing targeted amino acid substitutions at specific positions (particularly in CDR regions) within the human Vh3 framework to enhance binding affinity and diversity while preserving the overall human sequence background that reduces immunogenicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates composite antibody domains by combining human Vh3 framework regions with diversified CDR sequences, generating a hybrid structure that maintains human compatibility while achieving the binding diversity needed for therapeutic applications

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20250215616A1Variable heavy chain only libraries, methods of preparation thereof, and uses thereof

Publication Date: 2025.07.03 TAVOTEK BIOTHERAPEUTICS (HONG KONG) LTD

AI summary

The present disclosure relates to designs and applications of Variable Heavy Only (VHO) domain regions. The present disclosure provides a VHO library of polynucleotides encoding VHO domains, wherein the VHO domains are designed based on the Vh domain of a human Vh family, and a method of generating the VHO library. The present disclosure also provides a phage library displaying the VHO domains encoded by the VHO library through the use of M13 bacteriophage minor coat proteins such as pIX and pVII and a method of generating the phage library. The present disclosure also provides a method of screening the phage library to identify VHO candidates that are capable of binding a target of interest.