Split Effector Binding Molecules for Target-Dependent T Cell Activation
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Solution Overview
Problem
T cell bispecific antibodies face challenges in treating solid tumors due to on-target off-tumor cytotoxic activity and limited efficacy, primarily because of the lack of tumor-specific targets and instability of split CD3 binder domains, leading to aggregation and reduced expressibility.
Innovation Solution
A pair of binding molecules with complementary parts of an effector domain, where inert complementing domains stabilize and modulate the assembly equilibrium, forming a functional effector domain only when bound to target antigens, enhancing stability and production yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If split CD3 binder domains are used to reduce systemic toxicity, then therapeutic window is improved, but stability deteriorates leading to aggregation and reduced expressibility
Solution Approach 1:
The CD3 binder is divided into separate VL and VH domains that are expressed independently and assemble only upon binding to the target antigen, reducing systemic toxicity while maintaining stability through controlled assembly
Solution Approach 2:
Complementing domains are introduced as intermediaries that stabilize the individual VL and VH domains during circulation, preventing aggregation while allowing functional assembly when both binding domains are present on the target cell surface
2Stability of the object's composition
If complementing domains are added to stabilize individual binding domains, then stability and produceability are improved, but device complexity increases
Solution Approach 1:
The complementing domains serve multiple functions: stabilizing individual binding domains, preventing aggregation, and modulating assembly equilibrium, thereby improving stability without requiring multiple separate stabilization mechanisms
Solution Approach 2:
The complementing domains modify the physicochemical parameters of the individual binding domains (solubility, folding stability, half-life) to improve produceability and reduce aggregation while maintaining the ability to form functional effector domains upon antigen binding
3Object-affected harmful factors
If inert complementing domains are used to modulate assembly equilibrium, then target-dependent assembly is favored reducing off-tumor activity, but manufacturing complexity increases
Solution Approach 1:
The assembly equilibrium of the binding molecules is made dynamic and reversible, allowing the complex to form and dissociate based on local concentration and binding conditions, thereby favoring target-dependent assembly while simplifying purification processes
Solution Approach 2:
The complementing domains are designed to modulate the thermodynamic parameters of assembly (association/dissociation rates, equilibrium constants) to shift the equilibrium toward assembled states at target cell surfaces while maintaining solubility and stability during manufacturing and storage
Data Source
AI summary
The present invention relates to a pair of binding molecules comprising complementary parts of an effector domain, such binding molecules being capable of forming a functional effector domain when bound to their target antigens on the surface of a cell. Specifically, the invention relates to a pair of binding molecules wherein the complementary parts of the effector domain are complemented with inert complementing domains while the functional effector domain is not formed, providing advantageous properties, such as produceability, stability and/or biological functionality, to the binding molecules.