Humanized TGF-β1 Antibodies for Isoform-Selective Neutralization
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Solution Overview
Problem
Current therapies targeting TGF-β isoforms lack specificity, leading to potential immunogenicity and instability, and there is a need for humanized antibodies that can effectively neutralize TGF-β1 without affecting TGF-β2 or TGF-β3, particularly for cancer and fibrotic conditions.
Innovation Solution
Development of humanized antibodies that specifically bind and neutralize TGF-β1, while minimizing cross-reactivity with TGF-β2 and TGF-β3, utilizing specific CDR sequences for targeted therapeutic and diagnostic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies targeting TGF-β isoforms are used, then TGF-β signaling is inhibited, but specificity is lost leading to immunogenicity and instability
Solution Approach 1:
The patent segments the TGF-β family targeting approach by developing antibodies with isoform-specific binding. The humanized antibodies are designed to recognize unique epitopes on TGF-β1, TGF-β2, or TGF-β3 separately, allowing selective inhibition of specific isoforms rather than pan-TGF-β inhibition. This segmentation reduces immunogenicity by avoiding off-target effects on non-pathogenic isoforms.
Solution Approach 2:
The patent employs parameter changes by humanizing the antibody sequences - changing the amino acid composition and structural parameters of the antibody variable regions to achieve human-like characteristics. This reduces immunogenicity while maintaining binding affinity. Additionally, the antibodies are engineered with specific CDR region configurations to achieve isoform-selective binding parameters.
2Reliability
If current therapies targeting TGF-β isoforms are used, then TGF-β signaling is inhibited, but specificity is lost leading to instability
Solution Approach 1:
The patent applies parameter changes by optimizing the antibody structural parameters through humanization. The variable regions are engineered with human-like amino acid sequences and disulfide bond configurations, improving structural stability and reducing aggregation. The CDR regions are specifically designed to maintain conformational stability while achieving isoform-specific binding.
Solution Approach 2:
The patent creates composite antibody structures by combining human framework regions with engineered CDR regions. This composite approach integrates the stability of human antibody structures with the isoform-specific binding capabilities of the engineered regions, achieving both stability and specificity simultaneously.
3Object-affected harmful factors
If humanized antibodies are developed to bind TGF-β1 specifically, then immunogenicity is reduced, but cross-reactivity with TGF-β2 and TGF-β3 must be minimized
Solution Approach 1:
The patent applies local quality by designing CDR regions with specific local amino acid sequences that recognize unique epitopes on each TGF-β isoform. The CDR1, CDR2, and CDR3 regions are independently optimized to contact specific residues on TGF-β1, TGF-β2, or TGF-β3, achieving isoform-specific binding through localized sequence variations rather than global sequence changes.
Solution Approach 2:
The patent segments the binding interface by dividing the antibody-antigen interaction into distinct CDR regions, each responsible for recognizing specific features of the target isoform. This modular segmentation allows independent optimization of each CDR region to achieve high specificity for the desired isoform while maintaining humanized framework stability.
4Adaptability or versatility
If pan-TGF-β inhibition is used, then broad therapeutic coverage is achieved, but off-target effects on TGF-β2 and TGF-β3 occur
Solution Approach 1:
The patent segments TGF-β family targeting into isoform-specific therapies. Instead of using a single pan-TGF-β inhibitor, the invention provides separate humanized antibodies for TGF-β1, TGF-β2, and TGF-β3, allowing selective targeting of the pathogenic isoform while preserving the function of protective isoforms, thereby eliminating off-target effects.
Solution Approach 2:
The patent applies local quality by designing each antibody with CDR regions optimized for binding to the specific isoform's unique epitope. This localized optimization allows each antibody to selectively inhibit only its target isoform's signaling pathway, providing versatile therapeutic coverage for different conditions caused by different isoforms without cross-reactivity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The antibodies provide targeted therapeutic effects on cancer and fibrotic conditions by neutralizing TGF-β1, reducing immunogenicity and enhancing treatment efficacy with improved stability and specificity.
Implementation Method 1
humanized antibodies that specifically bind and neutralize TGF-β1
Data Source
AI summary
Antibodies, particularly humanized and variant antibodies and fragments thereof, which bind to TGF-β1 are provided, recognizing human and mouse TGF-β1, particularly that preferentially bind TGF-β1, including which do not recognize or bind TGF-β2 or TGF-β3. Humanized and variant antibodies provided are useful in the diagnosis and treatment of conditions associated with activated or elevated TGF-β1, including cancer, and for modulating immune cells and immune response, including immune response to cancer or cancer antigens, and in fibrotic conditions. The anti-TGF-β1 antibodies, variable regions or CDR domain sequences thereof, and fragments thereof may also be used in lymphoid cell-mediated, including T cell-mediated, therapy and/or combination with chemotherapeutics, immune modulators, or anti-cancer agents and/or with other antibodies or fragments thereof. Particular antibodies are exemplified herein, including antibodies 13A1-2A, 13A1-2B, 13A1-2C, 13A1-2D, 13A1-2E, 13A1-2F, 13A1-2G, 13A1-2H, 13A1-2I, 13A1-2J, 13A1-AF, 13A1-AG, 13A1-AH, 13A1-BF, 13A1-BG, 13A1-BH, 13A1-CF, 13A1-CG, 13A1-CH, 13A1-DF, 13A1-DG, 13A1-DH, 13A1-EF, 13A1-EG and 13A1-EH.