Zuben E. Sauna, Ph.D.
Laboratory of Hemostasis,
Division of Hematology,
Office of Blood Research and Review
Center for Biologics Evaluation and Research
- B.Sc. Ed. Bhopal University, India
- M.Sc. Poona University, India
- Ph.D. Poona University, India
- Years at FDA: 5
The development of neutralizing anti-drug antibodies (nADAs) to therapeutic-proteins can adversely affect the efficacy and safety of these drugs. There are also racial/ethnic disparities. For instance, in the treatment of hemophilia-A; prevalence of nADAs to the therapeutic protein (Factor-VIII) among African Americans is about twice that in Caucasians. Our recent work suggests that non-synonymous single nucleotide polymorphisms (ns-SNPs) in the endogenous (albeit nonfunctional) F8 could present risk-factors for the development of nADAs. By using an immunogenicity score we have developed we show that mutations, nsSNPs in the endogenous F8 gene and the HLA type may be biomarkers that explain the higher incidence of immunogenicity in African Americans. The methods we develop could have uses that go beyond race-based determinants of immunogenicity. For example, second- and third-generation therapeutic-proteins, which have been engineered to improve product attributes or to enhance process characteristics, are rapidly becoming the norm. Immunogenicity is a serious concern because engineered proteins include mutations, deletions and the introduction of linkers, junctions and fused polypeptides not normally found in nature and thus can potentially elicit immune responses. The computational, in vitro and ex vivo methods developed in our laboratory can raise red-flags early during the development process and also guide the planning of Phase III clinical trials. We are currently applying our methods to understand whether neo-epitopes generated during the design of two new Factor-VIIa analogs may have made them immunogenic. These two products were discontinued in Phase III trials due to immunogenicity in some (though not all) patients. If we can validate our approaches such individuals could be potentially identified in early stages of drug development opening the door to clinical trials based on pharmacogenetics. The major advantage of such an approach is that drugs such as these, which are highly beneficial and pose little or no risk to a great many patients, could be developed with a co-diagnostic that could identify individuals for who the drug is unsuitable.
Proposed Research Project for an FDA Commissioner's Fellow:
In addition to our published results on the increased incidence of nADAs among African Americans, we have initiated analysis of 192 Mexican American Founder Subjects (MAFS) who are part of the San Antonio Family Heart Study. Sequencing the F8 gene and high resolution HLA typing in these subjects offers an opportunity to benchmark the variability in the Mexican American population which may also be at increased risk of developing nADAs to Factor-VIII. For example our analysis of CDC data suggests a significantly increased risk for Hispanic Americans. However the size of the Hispanic population in this registry is very small (N=47) thus we also intend collecting and curating data from hemophilia treatment centers with large Hispanic Populations.
The FDA Regulatory Science Priority Area for the project is Stimulate Innovation in Clinical Trials and Personalized Medicine to Improve Product Development and Patient Outcomes.
Applicant should possess a Ph.D. or equivalent degree in molecular biology, immunology or bioinformatics. Our laboratory uses a diverse set of experimental approaches and computational strategies thus the ideal candidate will have the willingness to learn new techniques and approaches and operate outside his/her comfort zone. The laboratory is also very collaborative and thus it is import that the candidate be a team player. Candidates who have the inclination and motivation to try additional high-risk projects in addition to the primary project will receive full encouragement.
Selected Recent Publications:
- Yanover, C., Jain, N., Pierce, G.F., Howard, T.E. and Sauna, Z.E. Pharmacogenetics and the immunogenicity of protein therapeutics Nature Biotechnol. 29: 870-873, 2011.
- Sauna, Z.E. and Kimchi-Sarfaty, C. Understanding the contribution of synonymous mutations to human disease Nature Rev. Genet. 50: 683-691, 2011
- Pandey, G.S., Yanover, C., Howard, T.E. and Sauna, Z.E. Polymorphisms in the F8 Gene and MHC-II Variants as Risk Factors for the Development of Inhibitory anti-Factor VIII antibodies During the Treatment of Hemophilia A: A Computational Assessment. PLoS Comput. Biol. 9: e1003066, 2013.
- Pandey, G.S., Yanover, C., Miller-Jenkins, L.M., Garfield, S., Cole, S.A., Curran, J.E., Moses, E.K., Rydz, N., Simhadri, V., Kimchi-Sarfaty, C., Lillicrap, D., Viel, K., Przytycka, T., Pierce, G.F., Howard, T.E. and Sauna, Z.E. Synthesis of FVIII in Hemophilia-A patients with the intron-22-inversion may modulate immunogenicity. Nature Med. 19: 1318-1324, 2013.
- Kimchi-Sarfaty, C., Schiller, T., Katagiri, N, Khan, M., Yanover, M and Sauna, Z.E. Building better drugs: Developing and regulating engineered therapeutic proteins. Trends Pharmacol. Sci. 34: 534-548, 2013.