Nature‐Made Catalytic Antibody Platform: From Heisenberg's Uncertainty Principle to the Brink of Medical Interventions

Abstract

Specific target binding antibodies (Abs) are a $50 Bil/year industry. Quantum mechanics-based design of useful catalytic Abs (catabodies) failed because of the uncertain electronic structures of the dynamic and multiple charge-stabilized transition state catalyst-substrate complexes en route to product formation. We discovered harmful catabodies in autoimmune disease that catalyze self-protein hydrolysis by transient covalent pairing of a natural catabody nucleophile with weakly electrophilic target peptide bonds. The revelation of beneficial germline gene-encoded catabodies evolved by Darwinian natural selection was even more profound. Study of Ab inter-domain effects indicated upregulated variable (V) domain catalysis by ancient constant domain scaffolds (IgMs/single V domains; versus modern IgGs/paired V domains). The beneficial functional role of catabodies produced constitutively by healthy humans is evident from their specificity for: (a) toxic self-proteins that cause aging, and (b) nonself superantigen proteins of infectious microbes. Mining of libraries with non-hydrolyzable electrophilic target analogs (ETAs) yielded the best catabodies that convert the targets into harmless fragments. Superior catabody efficacy/safety compared to ordinary Abs is attributable due to rapid turnover/unstable target binding. We started commercial development of ex vivo-verified and in vivo-verified catabodies to dissolve brain, cardiac and vertebral amyloids (misfolded amyloid β, Tau, transthyretin). Weakened immunity to microbes in old age causes morbidity/death. In vitro-verified catabodies to HIV, HCV and drug-resistant S. aureus are in hand, including NIH designated Select Agents and biowarfare agents. Using the ETAs as immunogens bypasses key ordinary vaccine limitations. The ETAs accelerated deficient IgM→IgG class switching, corrected deficient synthesis of broadly neutralizing Abs, and induced catabody and irreversible Abs with enhanced target destruction capacity. Lead amyloid-directed catabodies and an HIV E-vaccine are ready for further IND-enabling toxicology and Phase 1 human trials. Support or Funding Information The studies were conducted mostly at the Univ of Texas Houston Medical School funded in part by Covalent Bioscience, the National Institutes of Health, SENS Research Foundation and Abzyme Research Foundation. The authors hold equity stakes in Covalent Bioscience. Failure of Pauling Transition State Analogs (TSAs), Birth of Nature-Made Catalytic Antibody (Catabody) Platform. E-Targets Enable Our CATABODY and E-VACCINE Platforms. Catabodies Outperform Ordinary Antibodies. First-In-Class Drug and Vaccine Development Potential. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.