MSLN/PD-L1 Nanobodies for Controlled T-Cell Activation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current nanobodies targeting MSLN or PD-L1 are inadequate, and T cell activating drugs for solid tumors face safety issues like cytokine release syndrome (CRS) and T cell dysfunction due to over-activation.
Innovation Solution
Development of nanobodies with specific sequences targeting CD3, MSLN, and PD-L1, combined with immunoglobulin Fc domains and peptide linkers, to modulate T cell activation and enhance anti-tumor effects while reducing cytokine release.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Weight of moving object
If traditional IgG heavy-light chain antibodies are used to target MSLN or PD-L1, then they have standard antibody structure and function, but they lack the advantages of small molecular weight, good stability, and strong permeability
Solution Approach 1:
The patent extracts only the essential antigen-binding function from the complete antibody structure by using single-domain antibodies (nanobodies) composed of a single variable domain (VHH) instead of the full IgG structure with both heavy and light chains. This extraction achieves reduced molecular weight while maintaining binding functionality.
Solution Approach 2:
The patent changes the structural parameters of the antibody by adopting camelid-derived VHH domains with unique properties (disulfide bond configuration, framework regions) that provide enhanced stability and permeability despite the reduced size, thus optimizing the weight-stability-permeability parameter set.
2Reliability
If CD3 bispecific antibody drugs are used to activate T cells for treating solid tumors, then T cell activation is achieved, but cytokine release syndrome (CRS) and T cell dysfunction occur due to over-activation
Solution Approach 1:
The patent applies local quality by creating a multispecific antibody where different domains have specialized functions: one domain targets CD3 for T cell engagement, another targets MSLN or PD-L1 for tumor specificity, and the structure is designed to provide moderate rather than maximal activation. This localized functional differentiation enables controlled T cell activation that reduces CRS and T cell dysfunction while maintaining anti-tumor efficacy.
Solution Approach 2:
The patent employs partial action by designing the CD3-binding domain to provide moderate T cell activation rather than full activation. The multispecific antibody structure enables sufficient anti-tumor response through partial activation, thereby avoiding the harmful effects of excessive T cell activation such as CRS and T cell dysfunction.
3Weight of moving object
If nanobodies are designed to target MSLN or PD-L1, then small molecular weight and good stability are achieved, but satisfactory nanobodies with effective anti-tumor activity are still lacking
Solution Approach 1:
The patent merges multiple functional domains into a single multispecific antibody molecule: VHH domains targeting MSLN and/or PD-L1 are combined with a CD3-binding domain (comprising VH and VL regions). This merging enables the nanobody to simultaneously achieve tumor antigen binding, T cell recruitment, and moderate activation, thereby providing effective anti-tumor activity despite the small molecular weight.
Solution Approach 2:
The patent implements multi-functionality by designing the multispecific antibody to perform multiple functions: (1) binding to tumor-associated antigens (MSLN, PD-L1) for tumor targeting, (2) binding to CD3 for T cell engagement, and (3) providing moderate T cell activation. This universal design enables a single molecule to address multiple requirements for effective cancer therapy.
Data Source
Figure 1A~1C
Figure 2~4
Figure 5~6b
AI summary
The present invention relates to a humanized single-domain antibody or an antigen-binding fragment thereof targeting MSLN or PD-L1. The present invention also relates to a multispecific antibody, and particularly provides a multispecific antibody targeting CD3, a tumor-associated antigen and an immune checkpoint, wherein the multispecific antibody has good medication safety and anti-tumor efficacy. The present invention further relates to use of the single-domain antibody or the multispecific antibody in disease treatment.