Multimerizing Antibodies for CD45 Cell Death
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Solution Overview
Problem
Current agents fail to effectively target and modulate CD45, a crucial protein involved in cellular responses, signaling, and immune regulation, leading to challenges in addressing autoimmunity, immunodeficiency, and malignancy, particularly in the context of cell transplantation where CD45-expressing cells need to be targeted without inducing significant cytokine release.
Innovation Solution
Development of binding molecules, specifically antibodies with altered formats such as IgG4 with knob-in-hole modifications and FcRn binding alterations, capable of multimerizing CD45 on target cells to induce cell death while minimizing cytokine release, including the use of mixtures of different binding molecules to enhance cross-linking and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known binding molecules are used to target CD45, then CD45 binding is achieved, but cell death induction is insufficient
Solution Approach 1:
The patent modifies the binding molecule structure to enhance CD45 cross-linking capability. Specifically, it uses antibodies with altered formats such as IgG4 with knob-in-hole modifications and FcRn binding alterations, which change the physical and chemical parameters of the binding molecule to improve its ability to multimerize CD45 and induce cell death.
Solution Approach 2:
The invention employs composite binding molecule structures combining different antibody formats and modifications. The use of IgG4 antibodies with knob-in-hole modifications creates a composite structure that enhances multimerization capability, and further combines FcRn binding alterations to achieve both improved cell death induction and controlled cytokine release.
2Reliability
If binding molecules are designed to multimerize CD45 to induce cell death, then cell death induction is improved, but cytokine release increases
Solution Approach 1:
The patent applies parameter changes by modifying the FcRn binding properties of the antibody. By altering FcRn binding, the molecule achieves optimized clearance and reduced immune activation, thereby inducing cell death through CD45 multimerization while minimizing harmful cytokine release.
Solution Approach 2:
The invention converts the potential harm of excessive cytokine release into a benefit by carefully tuning the antibody's FcRn binding properties. This allows the molecule to achieve sustained circulation and effective target engagement while avoiding excessive immune activation and cytokine storm, thus transforming a potential adverse effect into a controlled therapeutic advantage.
3Productivity
If standard IgG antibodies are used, then general binding capability is achieved, but multimerization efficiency of CD45 is insufficient
Solution Approach 1:
The patent changes the structural parameters of the antibody by using IgG4 format with knob-in-hole modifications. This structural parameter change enables enhanced multimerization of CD45 while maintaining a relatively simple and manufacturable antibody format, balancing complexity and functionality.
Data Source
AI summary
The present invention provides binding molecule or molecules that are able to multimerise CD45 to induce cell death of a cell expressing CD45 without also inducing significant cytokine release. For example, the invention provides antibodies against CD45, wherein the antibodies comprise at least two different paratopes each specific for a different epitope of CD45. The antibodies may be used to cross-link CD45 on the surface of cells. The antibodies may be used in a variety of therapeutic ways including to deplete cells, for example prior to cell transplantation.