Cummings School of Veterinary Medicine

Anti-infective VNAs

The Department of Infectious Disease and Global Health is developing a novel anti-infection platform employing VHH-based agents engineered for the prevention and treatment of infectious diseases, primarily for applications as enteric disease therapies. One anti-infective strategy is to engineer VHH-based neutralizing agents (VNAs) that interfere in the motility of pathogens or their ability to infect host cells. Where pathogens employ toxins to facilitate their infection of hosts, or to enhance their distribution to new hosts, we also employ Novel Antitoxin Agents. We are also developing VHHs that target pathogen or host factors as components of novel anti-infective enteric therapeutics, potentially delivered to the GI tract in various forms by probiotic or microbiome bacteria. This is a new area of research and is currently focused on the development of anti-infective agents for shigellosis, cryptosporidiosis and pathogenic E. coli such diarrheagenic E. coli/HUS and should permit rapid development and commercialization of safe, effective prophylactic and therapeutic agents with low development and production costs and long shelf lives. This project works in collaboration with the Bill and Melinda Gates Foundations, Lumen Biosciences, and the laboratories of Dr. John Leong, Dr. Cammie Lesser and Dr. Neel Joshi. For proof-of-concept testing of anti-infective VNAs we have ready access to the many animal models of enteric disease that are available within the Department of Infectious Diseases and Global Health.

Publications

  • Barta ML, Shearer JP, Arizmendi O, Tremblay JM, Mehzabeen N, Zheng Q, Battaile KP, Lovell S, Tzipori S, Picking WD, Shoemaker CB, Picking WL. 2017. Single-domain antibodies pinpoint potential targets within shigella invasion plasmid antigen D of the needle tip complex for inhibition of type III secretion. J Biol Chem. M117.802231.
  • Thran M, Mukherjee J, Pönisch M, Fiedler K, Thess A, Mui BL, Hope MJ, Tam YK, Horscroft N, Heidenreich R, Fotin-Mleczek M, Shoemaker CB, Schlake T. 2017. mRNA mediates passive vaccination against infectious agents, toxins, and tumors. EMBO Mol Med. e201707678.
  • Vrentas CE, Moayeri M, Keefer AB, Greaney AJ, Tremblay J, O'Mard D, Leppla SH, Shoemaker CB. 2016. A diverse set of single-domain antibodies (VHHs) against the anthrax toxin lethal and edema factors provides a basis for construction of a bispecific agent that protects against anthrax infection. J Biol Chem. 2016 Aug 18. pii: jbc.M116.749184.
  • Moayeri M, Tremblay JM, Debatis M, Dmitriev IP, Kashentseva EA, Yeh AJ, Cheung GY, Curiel DT, Leppla S, Shoemaker CB. 2016. Adenoviral expression of a bispecific VHH-based neutralizing agent targeting protective antigen provides prophylactic protection from anthrax in mice. Clin Vaccine Immunol. CVI.00611-15.
  • Sheoran AS, Dmitriev IP, Kashentseva EA, Cohen O, Mukherjee J, Debatis M, Shearer J, Tremblay JM, Beamer G, Curiel DT, Shoemaker CB, Tzipori S. 2014. Adenovirus vector expressing Stx1/2-neutralizing agent protects piglets infected with E. coli O157:H7 against fatal systemic intoxication. Infect Immun. 83:286-91.
  • Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, Chen K, Yu H, Tremblay JM, Chen X, Piepenbrink KH, Sundberg EJ, Kelly CP, Bai G, Shoemaker CB, Feng H. 2014. “A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice”. J. Inf. Dis. Sep 15;210(6):964-72.
  • Tremblay JM, Mukherjee J, Leysath CE, Debatis M, Ofori K, Baldwin K, Boucher C, Peters R, Beamer G, Sheoran A, Bedenice D, Tzipori S, Shoemaker CB. 2013. A single VHH-based toxin neutralizing agent and an effector antibody protects mice against challenge with Shiga toxins 1 and 2. Infect Immun. Dec;81(12):4592-603. doi: 10.1128/IAI.01033-13. Epub 2013 Sep 30.