Multimeric T Cell Engaging Molecule Asymmetric Potency
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Solution Overview
Problem
Current cancer therapies that engage effector cells, such as T cells, with tumor cells often result in overstimulation, leading to toxicity and cytokine release syndrome, necessitating a method that effectively targets tumor cells with minimal toxicity.
Innovation Solution
A method involving the administration of a multimeric T cell engaging molecule comprising five bivalent binding units with a modified J-chain and scFv molecule, specifically binding to CD20 and CD3, to selectively target and eliminate cancer cells while minimizing effector cell overstimulation, using dosing regimens that adjust based on administration-related symptoms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional T cell engaging antibodies are used to bridge tumor cells to effector cells, then tumor cell killing is achieved, but toxicity and cytokine release syndrome occur due to overstimulation
Solution Approach 1:
The patent applies local quality by creating binding units with asymmetric potency distribution - five binding units have high affinity for CD20 (tumor cells) while one binding unit has high affinity for CD3 (effector cells). This asymmetric design ensures that the effector cell engaging moiety has lower cumulative potency than the tumor targeting moiety, preventing overstimulation of effector cells while maintaining effective tumor cell killing through the high-affinity CD20 binding units.
2Productivity
If effector cell engaging moieties are designed with high potency to ensure strong T cell activation, then tumor cell elimination is enhanced, but toxicity increases due to excessive effector function stimulation
Solution Approach 1:
The patent applies parameter changes by carefully adjusting the affinity parameters of different binding units. The effector cell engaging binding unit is designed with lower affinity (higher KD) compared to the tumor targeting binding units. This parameter optimization ensures that the cumulative potency of effector engaging moieties remains lower than tumor targeting moieties, enabling sufficient tumor cell elimination while avoiding excessive effector cell activation and associated toxicity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method effectively treats cancer by selectively targeting and eliminating cancer cells with reduced toxicity and cytokine release, allowing for controlled and sustained therapeutic responses.
Implementation Method 1
a multimeric binding molecule comprising five bivalent binding units and a modified J-chain, where each binding unit comprises two IgM heavy chains, each comprising a heavy chain variable region (VH) and an IgM constant region and two light chains, each comprising a light chain variable region (VL) and a light chain constant region, where an associated VH and VL specifically bind to CD20 or a subunit thereof
Implementation Method 2
the modified J-chain comprises a J-chain or functional fragment or variant thereof and an scFv molecule that specifically binds to CD3
Data Source
AI summary
This disclosure provides methods of treating cancer comprising administering effector cell engaging molecules comprising one or more tumor targeting moieties and one or more effector cell engaging moieties. For example, the effector cell engaging molecules can have a greater cumulative potency for the tumor targeting moieties than the effector cell engaging moieties, the tumor targeting moieties can have greater avidity than the effector cell engaging moieties, and/or can be multimeric. The methods comprise, for example, administering different doses of effector cell engaging molecules based on the subject's symptoms and/or administering chimeric antigen receptor expressing cells.