To give us an expert insight into the paper recently published in Bioanalysis: Immunogenicity of antibody–drug conjugates: observations across 8 molecules in 11 clinical trials, author Montserrat Carrasco-Triguero (Genentech, CA, USA) answers some of our questions; discussing her inspiration and the next steps for her research.
I am a Senior Scientist at Genentech (CA, USA) where I manage a group that develops and runs immunoassays to assess product pharmacokinetics, host immune response and biomarkers of product effect such as activity and safety. Previously, I held positions at Genitope (CA, USA) and Chiron (CA, USA). I earned my Ph.D. in Pharmacy (Immunology program) from Universidad Complutense of Madrid, Spain.
I have over 20 years of experience in drug development. My work has contributed to characterizing biotherapeutic products and their fate in vivo. Additionally, I lead multi-functional pharmacology teams to advance biotherapeutics from research to clinical development and the market. I have authored documents for regulatory filings and published my work on immunogenicity. My interests include the application of new analytical technologies to overcome bioanalytical problems such as sensitivity and matrix effects as well as the incorporation of safety biomarkers in clinical studies.
Q What inspired you to work in this field of bioanalysis?
Since I was a pharmacy student, I have been interested in using different techniques to understand the biochemistry of human health and disease. Prior to joining the industry, I worked as a clinical chemist in a hospital laboratory using various analytical technologies. In addition to common laboratory tests, my work centered on the measurement of protein biomarkers to diagnose and monitor diseases such as autoimmune diseases, viral infections and cancer using immunoassay-based platforms. When I joined the industry, I could build on and apply my technical knowledge to the characterization of biotherapeutics so bioanalysis was a good fit for me.
My first experience evaluating immune responses to a drug involved a vaccine where formation of antibodies to the vaccine was expected at detectable levels. But developing assays to detect unwanted immune responses to biotherapeutics presented new challenges. For example, the assay format, assay sensitivity and interferences like the presence of the drug, receptors or the therapeutic target in the sample were important considerations during assay development to ensure that the assay could distinguish between true positive and negative samples.
I marvel at the continuous challenges that we encounter when developing anti-drug antibody (ADA) assays. Even though we have a default immunoassay platform that we can use across biotherapeutics as well as having a wealth of information that can help us overcome common analytical problems, every new biotherapeutic comes with specific needs that are often due to its modality and its target disease population. I enjoy finding the appropriate analytical solutions for each program and evaluating clinical immunogenicity data at the end of a study when the data are revealed and we hope the immunogenicity incidence will be low with no impact on exposure or safety.
Q What impact would you like to see/expect to see as a result of your publication?
There is limited published data on the clinical immunogenicity of antibody-drug conjugates (ADCs). This manuscript will enrich it by presenting the immunogenicity strategy and clinical data produced for eight ADCs targeting oncology indications. Additionally, the data indicate that in oncology clinical trials, classifying ADAs as persistent is inadequate because in most patients the duration of treatment is short.
The presence of non-natural components in the structure of ADCs theoretically increases their immunogenicity risk. However, this manuscript shows that patient immune responses to eight ADCs were similar to those observed with monoclonal antibody therapeutics, although it is worth noting that these results should not be extrapolated to all ADCs.
Q What are the next steps for your research and this field of bioanalysis?
In addition to ADCs, I work with other antibody-derived therapeutics. These molecules are becoming more complex; they may bind to multiple antigens as seen with bispecific antibodies or they may carry mutations to improve properties such as effector functions or pharmacokinetics. These engineered antibodies may present a higher immunogenicity risk than plain monoclonal antibodies so appropriate strategies and assays are needed to characterize their immunogenicity. In addition, I am excited about working with novel modalities requiring different types of delivery systems where immunogenicity strategies involve not only the active therapeutic but also the delivery system and other immune responses.
Q Are there any researchers/projects/technologies that you are watching at the moment, and any you think we should be keeping an eye on?
For over a decade, predictive immunogenicity tools have been developed and used preclinically to mitigate clinical immunogenicity by introducing modifications in the protein sequence that could reduce a T cell response and hence, clinical immunogenicity. Although I am interested in how this field is evolving, I am most interested in the associations between genetics and immunogenicity in the clinic. For example, specific HLA polymorphisms have been associated with increased risk for immunogenicity in patients treated with IFN-beta products or those receiving replacement therapies such as factor VIII. Genetic data will become a tool to inform not only biotherapeutic treatment options but also to prevent immunogenicity.
Q Do you have any advice for anyone who may be interested in working in this field?
My general advice is to stay curious, explore and learn from your colleagues. Understanding the biology of the disease and the effect of the biotherapeutic are important considerations for assay development. Of course, knowledge of different types of technologies that can be applied to a variety of therapeutic modalities is essential as well as being prepared for the changes in our industry.