Applied Microbiology

Biography

Biography: Jamshid Tanha

Abstract

Clostridium difficile continues to be one of the most prevalent hospital-acquired bacterial infections in the developed world, despite the recent introduction of a novel and effective antibiotic agent (fidaxomicin). Alternative approaches under investigation to combat the bacteria include fecal transplantation therapy, vaccines and antibody-based passive immunotherapies. By and large, inhibitory antibodies that recognize the primary C. difficile virulence factors, toxin A and toxin B, are the most popular passive immunotherapy under investigation, but antibodies to other targets, such as surface-layer proteins (SLPs), binary toxin, motility factors, and adherence and colonization factors may also have (complementary) therapeutic potential. Single-domain antibodies derived from camelid heavy chain antibodies and referred to as VHHs provide attractive therapeutic modalities against C. difficile infection (CDI). Some of their unique features compared to mAbs include their single-domain nature, small size (13-15 kDa), high chemical, thermal and proteolytic stability, high aggregation resistance, high level expression in microorganisms, high modularity, ability to access cryptic epitopes (e.g., cavities in receptors, enzymes, toxins and infectious agents), amenability to in vitro selection and engineering approaches for robust domains that are resistant to proteases (e.g., GI protease) and acidic pH-induced aggregation, denaturation and degradation. Moreover, high-affinity VHHs with KDs in the low-nM-pM range are readily obtainable. In my talk, I will describe our recent efforts to develop toxins A/B-specific and Ab-based therapeutics for CDI and how various antibody engineering approaches and structural data is used to improve their efficacy. Data on VHHs against another therapeutic target, C. difficile SLP are also presented.