Multi-Specific Binding Proteins for Low-HER2 Cancer Treatment
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Solution Overview
Problem
Current cancer treatments, particularly those targeting HER2-overexpressing cancers, face challenges in managing infusion-related reactions and are ineffective for cancers with low or moderate HER2 expression levels.
Innovation Solution
The use of multi-specific binding proteins that bind NKG2D, CD16, and a tumor-associated antigen like HER2, combined with corticosteroids, to treat cancers with low or moderate HER2 expression, and formulated into stable pharmaceutical compositions for subcutaneous administration to reduce infusion-related reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multi-specific binding proteins are administered to treat cancer, then treatment efficacy is improved, but infusion-related reactions occur
Solution Approach 1:
Corticosteroids are administered before the multi-specific binding protein to prevent infusion-related reactions. The preliminary administration of corticosteroids primed the immune system and reduced the severity of adverse reactions without compromising the anti-tumor efficacy of the binding protein
Solution Approach 2:
Corticosteroids serve as an intermediary substance that mediates between the multi-specific binding protein and the patient's immune system. They reduce the harmful immune activation caused by the binding protein while allowing the therapeutic effect to proceed
2Reliability
If conventional HER2-targeting treatments are used, then high HER2 expression cancers are treated effectively, but cancers with low or moderate HER2 expression are not effectively treated
Solution Approach 1:
The multi-specific binding protein is designed to function across multiple HER2 expression levels (low, moderate, and high) by combining HER2 targeting with immune cell engagement mechanisms. The protein maintains therapeutic efficacy regardless of HER2 expression level by activating NK cells and T cells through NKG2D and CD16 binding
Solution Approach 2:
The binding protein dynamically adapts its mechanism of action based on HER2 expression levels. For high HER2 expression, it provides direct targeting, while for low or moderate expression, it relies more heavily on immune cell activation through alternative pathways, making the treatment flexible and effective across different tumor contexts
3Ease of operation
If multi-specific binding proteins are formulated at high concentration, then subcutaneous administration is enabled and infusion-related reactions are reduced, but formulation stability challenges arise
Solution Approach 1:
The formulation parameters were optimized to enable high concentration (100 mg/mL) stability. This included adjusting pH to 5.5-6.5, selecting specific excipients (histidine, sucrose, polysorbate 80), and controlling ionic strength to prevent aggregation and maintain protein stability at the elevated concentration required for subcutaneous dosing
Data Source
AI summary
This disclosure relates to methods of treating cancer using multi-specific binding proteins that bind NKG2D, CD16 and a tumor-associated antigen such as HER2. Provided are uses of the multi-specific binding protein in combination with a corticosteroid to reduce the risk of infusion-related reactions. Also provided are uses of the multi-specific binding protein in treating cancer that has low or moderate HER2 expression level. The present disclosure also relates to pharmaceutical formulations comprising the multi-specific binding proteins.