Dr. Jeffrey Victor Leyton

Biography

Dr. Leyton’s PhD specialized in antibody engineering and his postdoctoral training focused on antibody-conjugate development. With extensive expertise in these fields, he has dedicated his research to the study and discovery of nuclear-targeting strategies for antibody-based therapeutics and beyond. His primary focus lies in designing innovative nuclear localization signals and elucidating new mechanisms of nuclear transport. These findings are then applied to the development of novel nuclear-targeted therapeutics to combat cancer and other diseases. Dr. Leyton’s concepts have paved the way for an improved understanding of how therapeutics can better escape endosome entrapment, achieve improved intracellular access or targeting of the nucleus, and are being commercially adapted as pharmaceutical products soon to enter human clinical trials. As a renowned expert in the field, Dr. Leyton’s research has been published in numerous scientific journals and has received recognition from the academic community and pharmaceutical industry. Driven by a commitment to advancing the field of nuclear-targeted medicines, Dr. Leyton is passionate about making a meaningful impact on patient care.

Expertise

• Antibody engineering and antibody-based therapeutic design
• Medical imaging and radiobiology principles
• Cancer research
• Nuclear localization signal computational design
• Molecular pharmacology

Research Projects 

The nucleus, containing vital genetic material necessary for cell survival, serves as the control center of a cell. It has become a major focus in therapeutic research due to its susceptibility to interventions. For instance, a significant portion of approved oncology drugs exert their effects inside the nucleus. Targets within the nucleus extend beyond the DNA double helix to include DNA-interacting proteins like Topoisomerase I, RNA polymerase II, and various kinases. Given the rising rates of drug resistance, targeted nuclear import is a highly effective approach to maximize cytotoxicity and minimize off-target effects.

Nuclear-targeting systems, utilizing nuclear localization signal (NLS) motifs, have made significant progress since the turn of the millennium when Dr. Gunter Blobel was awarded the Nobel Prize in Physiology in 1999 for his discovery of intrinsic signals that govern protein transport and localization within cells. Importins, nuclear transport receptors, recognize and bind NLSs, facilitating their import through the cytosol, passage through the nuclear pore complex, and entry into the nucleus. Numerous NLS-based therapeutic systems have been developed for treating cancer, chronic diseases, and infectious diseases, including COVID-19. However, the efficiency of nuclear localization remains a challenge, limiting the widespread impact of NLS-based therapeutics in healthcare.

Dr. Leyton’s research program aims to enhance treatment effectiveness by specifically targeting the nucleus of tumor cells. By focusing on this pivotal area, the program seeks to improve therapeutic outcomes and enhance patient well-being. Through the utilization of novel NLS sequences, computationally designed in-house, the program aims to optimize nuclear import efficiency and develop innovative NLS-based therapeutic systems. Moreover, Dr. Leyton’s research program emphasizes the importance of equity, diversity, and inclusion (EDI) by providing a safe and productive environment for student training and growth. Through EDI-focused student training, the program strives to magnify the positive impact of its advancements, ultimately benefitting a diverse and inclusive patient community in Canada and worldwide.

Brief description of research projects

CIHR-funded project: Reprogram intracellular transport to the nucleus to enhance tumor killing for antibodies conjugated to payloads active in the nucleus.

• Develop novel antibody-drug conjugates with various cytotoxic payloads active in the nucleus with novel nuclear localization signal (NLS) tags
• The NLS tags are computationally designed to improve circulation and intracellular barriers that have hampered NLS-tagged therapeutics in the past.
• Associate nuclear localization, accumulation and cytotoxicity.
• Capitalize on the power of positron emission tomography to evaluate pharmacokinetics, biodistribution, tumor uptake, and overall targeting.
• Determine the anti-tumor efficacy in preclinical models of cancer.

Publications

• Hammood M, Craig AW, and Leyton JV. Impact of endocytosis mechanisms for the receptors targeted by the currently approved antibody-drug conjugates (ADCs) – A necessity for future ADC research and development. Pharmaceuticals. 2021 Jul 15;14(7):674. Doi: 10.3390/ph14070674
• Bednova O and Leyton JV. Targeted molecular therapeutics in bladder cancer – A new and more effective option beyond the mixed fortunes of immune checkpoint inhibitors? International Journal of Molecular Sciences. 2020 Oct 1;21(19):7268. Doi: 10.3390/ijms21197268
• Lacasse V, Beaudoin S, Jean S, and Leyton JV. A novel and generalizable proteomic method reveals classical NLS-tagging of trastuzumab-emtansine contravenes classical nuclear transport in a model of HER2-positive breast cancer. Molecular Therapy-Methods &Clinical Development (Cell). 2020 Sep 1;19:99-119. Doi: 10.1016/j.omtm.2020.08.016
• Paquette M, Phoenix S, Lawson C, Guerin B, Lecomte R, Tai LH, Turcotte EE, and Leyton JV. A preclinical PET dual-tracer imaging protocol for ER and HER2 phenotyping in breast cancer xenografts. EJNMMI Res. 2020 Jun 26;10(1):69. Doi:10.1186/s13550-020-00656-8
• Leyton JV. Improving receptor-mediated intracellular access and accumulation of antibody therapeutics – the tale of HER2. Antibodies. 2020, 9, 32; Doi:10.33390/antib9030032
• Williams BA, Law A, Hunyadkurti J, Desilets S, Leyton JV, and Keating A. Antibody therapies for acute myeloid leukemia: Unconjugated, toxin-conjugated, radio-conjugated and multivalent formats. J. Clin. Med. 2019, 8(8):1261. Doi:10.3390/jcm8081261.
• Paquette M, Beaudoin S, Tremblay MA, Jean S, Lopez A, Lecomte R, Guerin B, Bentourkia M, Sabbagh R, and Leyton JV. NLS-cholic acid conjugation to IL-5Rα-specific antibody improves cellular accumulation and in vivo tumor-targeting properties in a bladder cancer model. Bioconjug. Chem. 2018, 29(4), 1352-1363. Doi:10.1021/acs.bioconjchem.8b00077.
• Paquette M, Vilera-Perez LG, Beaudoin S, Ekindi-Ndongo N, Boudreaut PL, Bonin MA, Battista MC, Bentourkia M, Lopez A, Lecomte R, Marsault E, Guerin B, Sabbagh R, and Leyton JV. Targeting IL-5Rα with antibody-conjugates reveals a strategy for imaging and therapy for invasive bladder cancer. Oncoimmunology. 2017, 6(10), e1331195.Doi :10.1080/2162402X.2017.1331195.
• Beaudoin S, Rondeau A, Martel O, Bonin MA, van Lier J, and Leyton JV. ChAcNLS, a novel modification to antibody-conjugates permitting target cell-specific endosomal escape, localization to the nucleus, and enhanced total intracellular accumulation. Mol. Pharm., 2016, 13 (6), 1915–26. Doi:10.1021/acs.molpharmaceut.6b00075.
• Leyton JV, Gao C, Williams B, Keating A, Minden M, and Reilly RM. A radiolabeled antibody targeting CD123(+) leukemia stem cells – initial radioimmunotherapy studies in NOD/SCID mice engrafted with primary human AML. Leuk. Res. Rep. 2015, 4(2):55-59. Doi:10.1016/j.Irr.2015.07.003.
• Leyton JV, Williams B, Gao C, Keating A, Minden M, and Reilly RM. MicroSPECT/CT imaging of primary human AML engrafted into the bone marrow and spleen of NOD/SCID mice using 111In-DTPA-NLS-CSL360 radioimmunoconjugates recognizing the CD123+/CD131- epitope expressed by leukemia stem cells. Leuk. Res. 2014, 38(11), 1367-73. Doi:10.1016/j.leukres.2014.09.005.
• Zereshkian A, Leyton JV, Cai Z, Bergstrom D, Weinfeld M, and Reilly RM. The human polynucleotide kinase/phophatase (hPNKP) inhibitor A12B4C3 radiosensitizes human myeloid leukemia cells to Auger electron-emitting anti-CD123 111In-NLS-7G3. Nucl. Med. Biol. 2014, 41(5), 377-83. Doi:10.1016/j.nucmedbio.2014.02.003.
• Leyton JV, Hu M, Gao C, Turner PV, Dick JE, Minden M, and Reilly RM. Auger electron radioimmunotherapeutic agent specific for the CD123+/CD131- phenotype of the leukemia stem cell population. J. Nucl. Med. 2011, 52(9):1465-73. Doi:10.2967/jnumed.111.087668.
• Leyton JV, Olafsen T, Sherman MA, Bauer KB, Aghajanian P, Reiter RE, and Wu AM. Engineered humanized diabodies for microPET imaging of prostate stem cell antigen-expressing tumors. Protein Eng. Des. Sel. 2009, 22(3):209-16. Doi:10.1093/protein/gzn055.
• Leyton JV, Olafsen T, Lepin EJ, Hahm S, Bauer KB, Reiter RE, and Wu AM. Humanized radioiodinated minibody for imaging of prostate stem cell antigen-expressing tumors. Clin. Cancer. Res. 2008, 14(22):7488096. Doi:10.1158/1078-0432.CCR-07-5093.

Awards and Nominations

• Mentor (2023), Banting Research Foundation
• Inventor (2017), Commercially successful worldwide patents
• Mentor (2021 and 2022), Reviewer-in-Training Program, CIHR
• Scientific Officer (2021 and 2022), Tri-Agency (CIHR, NSERC, SSHRC)
• Guest (Early Career Professor) (2019), 6th Annual Research and Postdoctoral Career Day
• Scientific Program Director (2017), GTCBio Antibody Protein Therapeutics Summit
• Laureate (2014), Banting Research Foundation
• Minority Scientific Scholar (2013), American Association for Cancer Research