Small CD28 Blocking Agents for Cleavage Inhibition in Immunotherapy
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Solution Overview
Problem
Existing immunotherapies, particularly those targeting the PD-1/PD-L1 axis, do not effectively address cancer in all patients and often lead to relapse, partly due to elevated levels of soluble CD28 (sCD28) that suppress immune activation and inhibit therapy efficacy.
Innovation Solution
Development of agents smaller than 100 kilodaltons that bind to membranal CD28 (mCD28) to inhibit proteolytic cleavage, thereby reducing sCD28 levels and enhancing immune activation, which can improve PD-1/PD-L1 based immunotherapy and treat cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PD-1/PD-L1 based immunotherapy is used to treat cancer, then immune activation is enhanced and cancer treatment efficacy is improved, but soluble CD28 (sCD28) levels remain elevated which suppresses immune activation and causes therapy relapse
Solution Approach 1:
The patent extracts and targets the specific harmful function of sCD28 by developing agents that bind to membrane-bound CD28 (mCD28) to prevent its proteolytic cleavage into soluble form. This extraction approach removes the root cause (mCD28 cleavage) rather than addressing the symptom (elevated sCD28 levels), thereby eliminating the harmful factor while preserving therapeutic benefits
Solution Approach 2:
The patent applies preliminary anti-action by using agents that prevent proteolytic cleavage of mCD28 before sCD28 can be generated. By blocking the cleavage site or preventing protease access to mCD28, the invention preemptively stops the formation of harmful soluble CD28, preventing immune suppression before it can occur during therapy
2Reliability
If full-length antibodies are used to block CD28 cleavage, then proteolytic cleavage is inhibited, but the antibodies are too large to access the membrane proximal region effectively
Solution Approach 1:
The patent segments the antibody molecule into smaller functional units (antibody fragments, nanobodies, single-domain antibodies) that retain CD28 binding capability while reducing size. This segmentation allows the agents to access the membrane proximal region where CD28 cleavage occurs, overcoming the accessibility limitation of full-length antibodies
Solution Approach 2:
The patent changes the size parameter of the blocking agent by using molecules smaller than 100 kilodaltons (such as Fab fragments, scFv, nanobodies, or single-domain antibodies) instead of full-length antibodies. This parameter change enables effective binding to membrane-bound CD28 while maintaining the ability to inhibit proteolytic cleavage
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 agents effectively inhibit proteolytic cleavage of mCD28, reducing sCD28 levels and enhancing immune activation, thus improving the efficacy of PD-1/PD-L1 immunotherapy and treating various cancers.
Implementation Method 1
agents smaller than 100 kilodaltons that bind membranal CD28 (mCD28) on a surface of a cell and inhibit proteolytic cleavage of the mCD28
Implementation Method 2
CD28 exhibits a mono-valent binding stoichiometry, while CTLA-4 interacts in a bivalent fashion. Hence, CTLA-4 binds B7 molecules with a much higher affinity and avidity than CD28
Data Source
AI summary
Agents that are less than 100 kilodaltons, bind a membranal immune receptor on a surface of a cell and inhibit proteolytic cleavage of the immune receptor are provided. Methods of treating cancer and improving immunotherapy comprising administering the agents are also provided.