Bispecific Molecule with Calmodulin Allosteric Switch
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Solution Overview
Problem
Bispecific antibodies, particularly those targeting CD3, face challenges with cytokine release syndrome (CRS) and other adverse effects due to overstimulation of the immune system, limiting their therapeutic effectiveness and safety in cancer treatment.
Innovation Solution
Development of a bispecific molecule with a first binding domain comprising a variable heavy chain region and a variable light chain region covalently connected by an allosteric switch linker containing a calmodulin polypeptide sequence, which binds to immune effector cells like T cells in the presence of calcium and a calmodulin binding ligand, allowing for regulated affinity and reduced adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific antibodies targeting CD3 are used to activate immune effector cells, then the ability to destroy tumor cells is improved, but cytokine release syndrome and other adverse effects occur due to immune system overstimulation
Solution Approach 1:
The patent applies dynamics by making the binding affinity of the bispecific molecule adjustable through allosteric modulation. The first binding domain's affinity to the immune effector cell antigen can be dynamically changed by binding of a modulating agent to the allosteric site, allowing the system to adapt its immune activation level rather than being fixed. This resolves the contradiction by enabling high efficacy when needed while allowing downregulation to prevent cytokine release syndrome.
Solution Approach 2:
The patent changes the binding affinity parameter of the first binding domain through allosteric modulation. By introducing an allosteric site that binds modulating agents, the binding strength between the first binding domain and its target antigen can be adjusted. This parameter change allows the system to optimize between sufficient immune activation for tumor destruction and reduced activation to avoid cytokine release syndrome.
2Adaptability or versatility
If bispecific antibodies are designed to bind to CD3 on immune effector cells, then the mechanism of action is improved, but the safety and versatility are limited due to inherent toxicity risks
Solution Approach 1:
The patent introduces an intermediary mechanism through the allosteric modulation system. The modulating agent acts as an intermediary that indirectly controls the binding interaction between the first binding domain and its target antigen. This intermediary control allows for safer regulation of immune activation, reducing direct toxicity risks while maintaining the desired mechanism of action for tumor targeting.
3Object-affected harmful factors
If conventional monospecific antibodies are used, then the safety profile is maintained, but the ability to achieve novel mechanisms of action and synergistic effects is lost
Solution Approach 1:
The patent applies dynamics by making the binding affinity of the bispecific molecule adjustable through allosteric modulation. The first binding domain's affinity to the immune effector cell antigen can be dynamically changed by binding of a modulating agent to the allosteric site, allowing the system to adapt its immune activation level rather than being fixed. This resolves the contradiction by enabling high efficacy when needed while allowing downregulation to prevent cytokine release syndrome.
Solution Approach 2:
The patent changes the binding affinity parameter of the first binding domain through allosteric modulation. By introducing an allosteric site that binds modulating agents, the binding strength between the first binding domain and its target antigen can be adjusted. This parameter change allows the system to optimize between sufficient immune activation for tumor destruction and reduced activation to avoid cytokine release syndrome.
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 bispecific molecule effectively targets immune effector cells while minimizing immune overstimulation, reducing the risk of cytokine release syndrome and enhancing the safety and versatility of bispecific antibody treatments.
Implementation Method 1
a first binding domain comprising a variable heavy chain region (VH) and a variable light chain region (VL) covalently connected by an allosteric switch linker comprising a calmodulin polypeptide sequence or a fragment, variant or a cyclic mutant thereof, wherein the first binding domain specifically binds an antigen on the surface of an immune effector cell in the presence of Ca+ and a calmodulin binding ligand
Implementation Method 2
an allosteric switch linker comprising a calmodulin polypeptide sequence or a fragment, variant or a cyclic mutant thereof
Data Source
AI summary
The disclosure provides bispecific molecules that comprise a first binding domain comprising a VH and VL connected by an allosteric switch linker comprising a calmodulin polypeptide sequence, and a second binding domain that specifically binds an epitope different from that bound by the first binding domain; and wherein the first binding domain specifically binds or releases an antigen on the surface of an immune effector cell in the presence of Ca+ and a calmodulin binding ligand. Pharmaceutical compositions containing the bispecific molecules, nucleic acids encoding the bispecific molecules, host cells containing the nucleic acids and methods of making and using the bispecific molecules are also provided.