Adoptive Cell Transfer Immunotherapy with IgG-Degrading Enzymes
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
The efficacy of adoptive cell transfer immunotherapies, such as CAR-T cell therapies, is limited by the survival and sustained activity of transferred cells due to antibody-mediated effector mechanisms, including CDC, ADCP, ADCC, and receptor activation-induced cell death, which are triggered by pre-existing and induced antibodies.
Innovation Solution
Administering proteins with IgG cysteine protease or IgG endoglycosidase activity, such as IdeS and EndoS, to inactivate these antibodies and enhance the survival and activity of transferred cells by mitigating antibody effector functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell transfer immunotherapy is administered, then tumor-specific cytotoxic activity is improved, but cell survival and sustained activity are reduced due to antibody-mediated effector mechanisms
Solution Approach 1:
The patent applies preliminary anti-action by administering IgG-degrading enzymes (such as IdeS or EndoS) before or at the time of adoptive cell transfer immunotherapy administration. These enzymes pre-emptively degrade anti-CAR antibodies and other IgG molecules in the patient's serum that would otherwise mediate harmful effector functions against the transferred CAR-T cells. This preliminary destruction of harmful antibodies prevents complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC), thereby extending CAR-T cell survival and persistence in the patient.
Solution Approach 2:
The patent converts the harmful effect of IgG antibodies into a beneficial outcome by using IgG-degrading enzymes to selectively destroy pathogenic anti-CAR antibodies while preserving the therapeutic function of CAR-T cells. The enzymes that would normally be seen as interfering with therapy are instead harnessed to eliminate the specific harmful antibodies causing cell destruction, thereby transforming a negative factor (humoral immunity) into a protective mechanism that enhances therapy durability.
2Quantity of substance
If CAR-T cells are expanded in vitro to high numbers, then tumor-specific cytotoxic potential is improved, but susceptibility to antibody-mediated destruction increases
Solution Approach 1:
The patent introduces IgG-degrading enzymes as intermediary agents that mediate protection between the expanded CAR-T cell population and the patient's humoral immune system. These enzymes act as a protective buffer, degrading anti-CAR antibodies and other IgG molecules that would otherwise directly attack the high-number CAR-T cell population. This intermediary mechanism allows the therapeutic benefit of high cell numbers to be realized while neutralizing the increased susceptibility to antibody-mediated destruction that comes with larger cell populations.
3Duration of action of stationary object
If repeat infusion of CAR-T cells is administered, then sustained tumor control is improved, but preexisting and induced humoral immunity increases
Solution Approach 1:
The patent applies preliminary action by administering IgG-degrading enzymes before repeat CAR-T cell infusions to pre-emptively clear preexisting anti-CAR antibodies from the patient's serum. This preliminary degradation of harmful antibodies creates a more favorable immunological environment for the repeat infusion, reducing the risk of rapid cell destruction and enabling sustained tumor control despite the presence of induced humoral immunity from previous treatments.
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 proteins increase the survival and activity of transferred cells by reducing antibody-mediated destruction and improving the binding of cell surface receptors to their targets, thereby enhancing the therapeutic effect of adoptive cell transfer immunotherapies.
Implementation Method 1
The immunoglobulin G-degrading cysteine protease, imlifidase (IdeS) is an IgG endopeptidase that is currently under development as a rapid desensitization treatment in kidney transplantation. Imlifidase is highly specific and cleaves all subclasses of human IgG.
Implementation Method 2
administering a protein that has IgG cysteine protease or IgG endoglycosidase activity
Data Source
Figure 1(A)
Figure 1(B)
Figure 1(C)
AI summary
The present invention relates to methods for enhancing adoptive cell transfer immunotherapy by administering a protein that has IgG cysteine protease or IgG endoglycosidase activity.