Cambridge Healthtech Institute’s Kent Simmons recently spoke with Dr. Christopher Nicodemus, Chairman of the OncoQuest Inc. Clinical & Scientific advisory board and Principal of AIT Strategies about his upcoming talk, “Indirect Immunization with Antigen Specific Monoclonal IgG & IgE: Schedule Dependent interactions with Cytotoxic Agents and Immune Modulators” to be presented at the Antibody Discovery Forum (Part 2) meeting at the 2018 Discovery on Target. Discovery on Target is scheduled for 25-28, 2018 in Boston, with Dr. Nicodemus’ talk set for the afternoon of Friday, September 28.
Indirect Immunization is not a term commonly discussed in antibody discovery forums. Is this application of antibodies widely appreciated?
We have coined this expression to distinguish a method of immunization from the classical teaching of active and passive immunization---used to characterize vaccination strategies especially for infectious disease applications. The recent advances in the field of ImmunoOncology and elucidation of the myriad of overlapping or redundant pathways to counter-regulate active immune responses has made this use of descriptive language helpful to distinguish the technology being advanced at OncoQuest from other monoclonal antibody applications. As used in my presentation the term refers to limited intermittent administration of stoichiometric doses of self-antigen specific antibody in scheduled combination with other standard agents to induce and amplify an antigen specific immune response. The primary clinical application at this time is in cancer. The approach is not widely appreciated, but recent clinical progress has demonstrated the potential of this treatment approach.
Does target discovery for Indirect Immunization follow the same algorithms as classical monoclonal antibody target discovery?
The field of antibody engineering has focused on target specificity and de-immunization to generate the vast majority of pharmacologically dosed antibodies in advanced development or commercialized today. Innovative techniques to engineer bi-specificity and similar attributes focus on amplifying or blocking specific biologic pathways for therapeutic advantage. Target selection by the traditional approach is limited only by the innovators appreciation of gene expression and its relevance to cellular interactions. In contrast with indirect immunization one is using the inherent properties of specific immunoglobulin subtypes at physiologic doses to modulate immunity. The target of an indirect immunizing antibody is multifocal. The antibody of course has specificity for an antigen via its variable regions but the immune modulatory biology is driven by the characteristics of a given antibody’s Fc region. In fact every antibody in nature or engineered has pluri-specificity mediated through the FC elements contained in the individual molecule. OncoQuest is using non- standard FC region cassettes to influence biologic response in previously unappreciated ways distinct from the standard engineering approaches of used for pharmacologic dosing of monoclonal antibodies.
Can you describe the pipeline that the OncoQuest approach has generated?
OncoQuest has focused its R&D resources onto specific cancer applications although with improved appreciation of the relevance of these pathways additional applications in infectious disease and autoimmunity can be anticipated. The company has identified tumor antigens of interest and generated a series of products in each of two categories. The first uses murine Fc-γ isotypes and two of these products, specific to MUC1 and MUC16 are in clinical stage development. The company has also explored the biology of human Fc-ε and found a very promising additional set of properties associated with human epsilon. Three lead candidates are in the pre-IND stage using this second generation approach. These targets include Muc1, HER2/neu and PSA.
What is the advantage of antibody constructs containing human Fc epsilon constant regions?
OncoQuest has found that human Fc-epsilon not only serves as a potent means to induce antigen cross presentation of self-antigen, relief of tolerance and induction of potent T cell immunity but it also modulates the phenotypic behavior of myeloid derived cells inducing additional anti-tumor cellular pathways that cannot be addressed using the immunoglobulin gamma receptor pathways.
What are the clinical implications of your work?
Much of the discovery made in the OncoQuest program is derived from human clinical trials using prototypic constructs and a lack of understanding of the profound interactions that concomitant standard therapies have on altering immune responsiveness. The current IND pipeline is designed and prioritized based on clinical findings from the lead program targeting MUC16 and human transgenic models for the secondary products. Based on results presented at ASCO in 2017, the company believes that scheduled indirect immunization with select standard chemotherapeutic agents can profoundly alter the magnitude of the immune component of a therapeutic response to treatment. This will result in an ability to substantially reduce the required exposure to cytotoxic agents and through low dose indirect immunization achieve a clinical benefit greater than previously achievable with reduced toxicity. This will be a second paradigm shift in clinical practice of immune-Oncology as multimodality combinatorial therapy designed to maximize the immune contribution to clinical effect extends disease free intervals and reduces the exposure to toxic therapeutic cancer drugs. A phase III demonstration in ovarian cancer is getting underway.
Christopher F. Nicodemus, MD, Chairman, Clinical & Scientific Advisory Board, OncoQuest, Inc., Canada
Dr. Nicodemus is a graduate of Harvard College and received his doctorate from SUNY Syracuse. His career interest has been in experimental medicine and applied clinical immunology. He is a fellow of the American College of Physicians who received his post-doctoral training in medicine and clinical immunology at Harvard. He is an alumnus of the Austen laboratory at Brigham and Women’s Hospital in Boston, has held faculty appointments at Harvard Medical School, and served in senior management positions in both Pharma and Biotech. He was the Founder, Chairman and Chief Scientific Officer of Advanced Immune Therapeutics, and is the Principal of AIT Strategies and Chairman of the Scientific and Clinical Advisory Board at OncoQuest,Inc. which is focused on innovative applications of monoclonal antibodies in therapeutic immunology.