Single-Domain GITR Agonists for Potent T Cell Activation
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Solution Overview
Problem
Current cancer treatments, particularly chemotherapy, have unsatisfactory cure rates and severe side effects, while the therapeutic efficacy of GITR agonists for cancer immunotherapy remains unclear, necessitating improved GITR agonists with specific functional properties for enhanced therapeutic effectiveness.
Innovation Solution
Development of polypeptides comprising immunoglobulin single variable domains (ISVDs) that specifically bind GITR, exhibiting improved efficacy with EC50 values of 200 pM or less, enhancing immune responses and inhibiting tumor cell growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy is used as a mainstay cancer treatment, then some success is achieved in treating cancer, but the cure rate remains unsatisfactory and severe side effects occur
Solution Approach 1:
The patent changes the therapeutic approach from chemotherapy to immunotherapy by developing GITR agonists with specific molecular parameters (EC50 values of 200 pM or less). This parameter change in treatment modality aims to improve cure rates while reducing the severe side effects associated with chemotherapy.
2Reliability
If agonistic monoclonal antibodies against GITR are used to promote anti-tumor immunity, then immune activation is enhanced, but the therapeutic efficacy remains unclear and needs improvement
Solution Approach 1:
The patent applies parameter changes by optimizing the molecular structure of GITR agonists to achieve EC50 values of 200 pM or less. This quantitative improvement in binding affinity and potency directly addresses the unclear therapeutic efficacy by providing measurable, high-performance agonists with defined functional parameters.
3Reliability
If conventional antibodies are used for GITR activation, then immune response is stimulated, but the cost is high and stability needs improvement
Solution Approach 1:
The patent extracts the essential antigen-binding function from conventional antibodies by using only the immunoglobulin single variable domain (ISVD). This extraction eliminates the need for producing entire antibody molecules, thereby reducing manufacturing costs and improving stability while retaining the core therapeutic function of GITR activation.
Solution Approach 2:
The patent employs ISVDs as simplified, cost-effective alternatives to full-length antibodies. These truncated immunoglobulin domains are cheaper to produce and manufacture, providing an economically viable solution that maintains therapeutic efficacy while reducing production costs.
Data Source
Figure 1A~1C
Figure 1D~2B
Figure 3~4B
AI summary
The present invention relates to immunoglobulin single variable domains that bind GITR and more in particular to polypeptides that comprise or essentially consist of one or more such immunoglobulin single variable domains; to nucleic acids encoding such polypeptides; to methods for preparing such polypeptides; to compositions and in particular to pharmaceutical compositions that comprise such polypeptides, for prophylactic, therapeutic or diagnostic purposes. In particular, the polypeptides of the present invention enhance the biological activity of GITR.