Heterodimeric Proteins for Selective Treg Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for modulating T cells, particularly in cancer and autoimmune diseases, face challenges in selectively targeting regulatory T cells (Tregs) due to the lack of specific surface markers and the non-selective effects of existing therapies like IL2 administration, which can suppress or promote both effector and Treg populations, leading to adverse side effects.
Innovation Solution
Development of bispecific antibodies and heterodimeric proteins that specifically target CD25, CD4, CD8, CCR4, GITR, or PD-1, with variant Fc domains to selectively suppress or stimulate Treg and cytotoxic T cells, minimizing impact on other T cell types, using amino acid substitutions and specific antigen-binding domains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If anti-CD25 antibodies or IL2-DT fusions are used to target Treg cells, then Treg depletion is achieved, but activated effector T cells are also depleted
Solution Approach 1:
The patent applies local quality by creating heterodimeric proteins with asymmetric structure where one monomer contains an anti-CD25 binding domain and the other contains a different Treg-specific binding domain. This asymmetric design allows the protein to target Treg cells through dual recognition of CD25 and another Treg marker, achieving selective Treg depletion without affecting effector T cells that only express CD25 upon activation
Solution Approach 2:
The invention uses composite materials by constructing heterodimeric proteins composed of two different monomers with distinct binding specificities. One monomer binds to CD25 while the other binds to a second Treg-specific marker, creating a composite targeting system that recognizes multiple Treg surface markers simultaneously, thereby achieving selective Treg targeting without cross-reactivity with effector T cells
2Productivity
If systemic IL2 administration is used to promote effector T cell expansion, then cytotoxic T cell response is enhanced, but Treg population is also promoted and severe toxicities occur
Solution Approach 1:
The patent extracts the harmful systemic effects of IL2 by using heterodimeric proteins that specifically target Treg cells for depletion rather than systemically administering IL2 to expand all T cells. The heterodimeric proteins are designed to bind specifically to Treg surface markers (CD25 and another Treg-specific marker) and mediate selective Treg depletion through antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, thereby avoiding the vascular leak syndrome and other toxicities associated with systemic IL2 administration
Solution Approach 2:
The invention uses heterodimeric proteins as intermediaries to achieve Treg depletion without requiring systemic IL2 administration. These proteins serve as mediators that specifically recognize and eliminate Treg cells through their dual binding domains, providing an alternative mechanism to IL2-based Treg modulation that avoids the harmful side effects while still achieving the desired shift in the effector-to-Treg cell balance
3Measurement precision
If anti-CD25 antibodies are used to block IL2-mediated T cell expansion, then Treg numbers are reduced, but effector T cell responses are also suppressed
Solution Approach 1:
The patent applies local quality by designing heterodimeric proteins with asymmetric binding specificities where one monomer targets CD25 and the other targets a second Treg-specific marker. This localized dual-targeting approach ensures that only cells expressing both markers (Treg cells) are depleted, while effector T cells that only express CD25 upon activation are spared, thereby avoiding suppression of effector T cell responses
Solution Approach 2:
Instead of using anti-CD25 antibodies that broadly suppress all CD25-expressing T cells (including effector T cells), the invention inverts the approach by using heterodimeric proteins that require simultaneous binding to CD25 and a second Treg-specific marker. This inverted strategy transforms the non-selective CD25 targeting into a selective Treg-targeting system by adding the requirement for dual marker expression
Data Source
AI summary
The present invention relates to methods and compositions for modulating T cells. The modulation includes suppressing or inducing regulatory T cells or cytotoxic T cells.