Humanized Anti-GITR Antibodies for Specific Immune Modulation
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Solution Overview
Problem
Current methods for treating immune and proliferative disorders, such as tumors and cancers, lack specificity and efficacy in modulating Glucocorticoid-induced TNF receptor (GITR) activity, requiring improved agonists with high affinity and specificity for GITR that can stimulate signaling at low doses without interfering with other receptors, and are suitable for both cytotoxic and non-cytotoxic applications.
Innovation Solution
Development of humanized anti-GITR monoclonal antibodies with specific CDR sequences that bind to human GITR, capable of blocking GITR-mediated activity and enhancing immune responses, which can be used alone or in conjunction with TGFβ antibodies and local radiation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional methods are used to treat immune and proliferative disorders, then treatment can be provided, but the methods lack specificity and efficacy in modulating GITR activity
Solution Approach 1:
The patent employs parameter changes by developing humanized anti-GITR antibodies with optimized CDR sequences that achieve high affinity binding to GITR. The antibodies are engineered with specific amino acid sequences in the complementarity determining regions to enhance binding strength and specificity, thereby improving efficacy while maintaining targeted action against GITR without affecting other receptors.
Solution Approach 2:
The humanized anti-GITR antibodies serve as intermediaries that specifically bind to GITR on T cells and dendritic cells. These antibodies mediate the desired immune modulation by interacting with GITR to stimulate signaling pathways, providing a targeted mechanism to enhance anti-tumor immunity and treat immune disorders with high specificity.
2Reliability
If high doses of agonists are used to stimulate GITR signaling, then signaling can be activated, but the affinity requirement cannot be met at relatively low doses
Solution Approach 1:
The patent achieves potent GITR signaling activation at low doses by optimizing the binding parameters of the anti-GITR antibodies. The humanized antibodies are engineered with enhanced affinity for GITR through careful selection of CDR sequences, allowing effective signaling activation at lower concentrations compared to conventional agonists.
3Reliability
If antibodies are used to treat immune disorders, then GITR activity can be modulated, but antigenicity may be generated when administered to subjects
Solution Approach 1:
The patent extracts the essential antigen-binding functionality from non-human antibodies by transferring only the critical complementarity determining region (CDR) sequences to a human antibody framework. This humanization process removes the immunogenic non-human portions while retaining the ability to bind GITR, thereby reducing antigenicity when administered to human subjects.
Solution Approach 2:
The patent applies local quality by humanizing specific regions of the antibody molecule. The CDR sequences, which are responsible for antigen binding, are derived from non-human antibodies to maintain GITR binding capability, while the framework regions are humanized to reduce immunogenicity. This localized approach preserves functionality while minimizing harmful antigenic effects.
4Reliability
If agonists are designed for high specificity to GITR, then other receptors are not interfered with, but the complexity of achieving such specificity increases
Solution Approach 1:
The patent achieves high specificity for GITR by optimizing the CDR sequence parameters of the humanized antibodies. Through iterative design and selection of specific amino acid sequences in the CDR regions, the antibodies are engineered to recognize and bind GITR with high affinity and specificity, distinguishing it from other TNFR superfamily members without requiring overly complex molecular structures.
Data Source
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AI summary
Antibodies to human GITR are provided, as well as uses thereof, e.g., in treatment of proliferative and immune disorders.