The past two-plus decades have witnessed an explosion of research into the development of monoclonal antibodies (mAb) for therapies ranging from cancer and autoimmunity to transplantation, thrombosis and drug addiction. At least 35 such mAb have obtained FDA approval, and many more are in various stages of development and evaluation. A recurring issue with mAb therapy is that patients frequently generate immune responses against the mAb, often reducing their effectiveness, sometimes with serious consequences. Due to the proteinaceous nature of the therapy, these reactions to passive mAb therapy are dependent upon CD4 T cells that perceive part of the mAb as foreign. These reactions still occur despite extensive efforts to eliminate foreignness from the mAb heavy and light chain polypeptides. Even fully human mAb, derived from human antibody genes expressed in mice or from phage display libraries of human antibody genes, can be perceived as foreign by human CD4 T cells due to extensive CDR3 diversity and somatic mutations. Eliminating these somatic alterations is risky because they are often necessary for conferring a high binding affinity to the mAb. My laboratory has many years of experience with somatic hypermutation and CD4 T cell cognition and responses to mutated sequences within V regions of soluble immunoglobulin and B cell receptors. We are well-positioned to exploit this experience and recent progress to develop a strategy for generating reagents that can induce tolerance to mAb in the CD4 T cell repertoire, so that unwanted immune reactions to therapeutic mAb can be averted. We will test the feasibility of our tolerance strategy in a well-defined mouse model. Our strategy is simple, can be applied to any mAb, and is expected to present few regulatory hurdles, enabling potential widespread clinical application.

Public Health Relevance

Monoclonal antibodies (mAb) are becoming a therapy of choice to treat many diseases and conditions, ranging from various cancers and autoimmunities to thrombosis and drug addictions. The FDA has approved over 35 such antibodies, with many more in various stages of development and under evaluation. A significant problem with mAb therapy is that patients often make immune reactions against the mAb because their immune systems perceive the mAb as a foreign entity. These anti-mAb immune reactions are sometimes dangerous, and almost always problematic because they neutralize the mAb and inhibit its therapeutic effects. Despite heroic efforts to 'humanize' these mAb by reducing their foreignness, these immune reactions still occur. Our project seeks to overcome this problem by developing a general strategy that can be used to 'educate' the patient immune system into 'thinking' that therapeutic mAb is a part of self, i.e. not foreign so that these unwanted immune reactions will not occur. We will test our strategy in a mouse model that is amenable to rigorous evaluation of efficacy. Our strategy is simple, and if successful, could see widespread application in the context of mAb therapy to avert these undesirable immune reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI121980-02
Application #
9199076
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Ferguson, Stacy E
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206