Induction of Immune Tolerance: Addressing Unmet Medical Need in Immune Mediated Diseases and Immune Responses to Biologics

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Background

Unwanted immunogenicity or the capacity of a biologic drug to induce cellular and humoral responses is a major hurdle to treatment success. These immune responses, mainly in the form of anti-drug antibodies (ADA), can partially or completely negate therapeutic efficacy and may lead to severe allergic reactions upon repeated exposure to the biologic drug. Hence, efforts to mitigate the risk of anti-drug antibody (ADA) development have been pursued. Often, these efforts focus on reducing the biologic products’ intrinsic immunogenicity attributes through removal of CD4 T and B cell epitopes. However, this sequence-based de-immunization process might not always be applicable such as in the case of enzyme replacement therapies where amino-acid modifications can result in the decrease or even loss of activity of the drug. ADA development to monoclonal antibody-drugs (mAbs) have also been found to lead to loss of response through drug inhibition and/or enhanced drug clearance. Beyond loss of efficacy, ADA development raises additional safety concerns including immune complex-mediated toxicity observed in preclinical studies and hypersensitivity reactions. Frequently, loss of clinical response to mAbs therapy leads to drug switching in patients. In the case of gene therapy, pre-existing immunity (humoral and cellular) to the viral capsid of adeno-associated viral vectors is an exclusion criteria for patient eligibility for treatment and can lead to loss of therapeutic benefit; moreover treatment-induced neutralizing antibodies are prohibitive to vector re-administration, creating a major obstacle to treatment success. Similarly, allogeneic immune rejection of hESC-derived cells by recipients of cell therapy requires immune tolerance regimens beyond the conventional immune suppressants like modulating the costimulatory and inhibitory pathways responsible for T cell activation. In this context, approaches to induce antigen-specific tolerance to mAbs, replacement protein drugs and advanced therapy medicinal products would be transformative. ADA mediated clearance and therefore decreased exposure in toxicology animal studies has also been a challenge in drug development and would benefit from tolerance induction regimens.

In this Research Topic, we want to cover the current status of induction of tolerance to mitigate clinical immunogenicity of biologics, including gene and cell therapy. We aim to present studies, which describe innovative methods and agents for inducing specific and non-specific immune tolerance to biologics, describe investigations into the mechanisms underlying the development of such responses, discuss the benefit of approaches already in the clinic and the promises of novel methods currently at the pre-clinical development stage.

We welcome the submission of Mini Reviews, Reviews, Original Research Articles and Methods Articles covering, but not limited to, the following sub-topics:

- Current methods of tolerance induction to gene therapy products
- Current approaches to circumvent immunogenicity of replacement therapy products
- Pre-clinical models of tolerance induction to biologics
- Antigen-specific tolerance
- Innovative approaches to tolerance induction
- Reversion of pre-existing immunity
- Biomarkers of tolerance induction in the clinic

Dr. Sophie Tourdot is an employee of Pfizer Inc. Dr. Markusic research laboratory receives financial support from Pfizer Inc. The other Topic Editors declare no conflict of interest with regards to the Research Topic theme

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