Nature-Made Catalytic Antibody Platform: From Heisenberg’s Uncertainty Principle to the Brink of Medical Interventions
Sudhir Paul, Stephanie Planque and Richard Massey
Covalent Bioscience Inc, Houston, Texas, USA
Specific target binding antibodies (Abs) are a $50 Bil/year industry. Quantum mechanics-based design of useful catalytic Abs (catabodies) failed because the electronic structure of the dynamic catalyst-substrate complex is uncertain. We discovered harmful catabodies in autoimmune disease that catalyze self-protein hydrolysis by transient covalent pairing of the catabody nucleophile with a target electrophile. The revelation of beneficial germline gene-encoded catabodies evolved by Darwinian natural selection was even more profound. Catalysis by the Ab variable (V) domains is upregulated by ancient scaffolds (IgMs/single V domains; versus modern IgGs/paired V domains). Healthy humans produce beneficial catabodies specific for: (a) toxic self-proteins that cause aging and (b) nonself superantigen proteins of infectious microbes. Mining of libraries with electrophilic target analogs (ETAs) yields the best catabodies that convert targets into harmless fragments. Superior catabody efficacy/safety is due to rapid turnover/unstable target binding confer compared to ordinary Abs. We started commercial development of ex vivo- 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. Using the ETAs as immunogens bypasses key ordinary vaccine limitations. The ETAs accelerate deficient IgM→IgG class switching, correct deficient synthesis of broadly neutralizing Abs, and induce catabody and irreversible Abs with enhanced target destruction capacity. Lead catabody medicines are ready for development.
Conflict of interest: The authors hold equity stakes in Covalent Bioscience. The studies were funded in part by Covalent Bioscience, the National Institutes of Health, SENS Research Foundation and Abzyme Research Foundation.
Covalent Bioscience Inc, Houston, Texas, USA
Specific target binding antibodies (Abs) are a $50 Bil/year industry. Quantum mechanics-based design of useful catalytic Abs (catabodies) failed because the electronic structure of the dynamic catalyst-substrate complex is uncertain. We discovered harmful catabodies in autoimmune disease that catalyze self-protein hydrolysis by transient covalent pairing of the catabody nucleophile with a target electrophile. The revelation of beneficial germline gene-encoded catabodies evolved by Darwinian natural selection was even more profound. Catalysis by the Ab variable (V) domains is upregulated by ancient scaffolds (IgMs/single V domains; versus modern IgGs/paired V domains). Healthy humans produce beneficial catabodies specific for: (a) toxic self-proteins that cause aging and (b) nonself superantigen proteins of infectious microbes. Mining of libraries with electrophilic target analogs (ETAs) yields the best catabodies that convert targets into harmless fragments. Superior catabody efficacy/safety is due to rapid turnover/unstable target binding confer compared to ordinary Abs. We started commercial development of ex vivo- 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. Using the ETAs as immunogens bypasses key ordinary vaccine limitations. The ETAs accelerate deficient IgM→IgG class switching, correct deficient synthesis of broadly neutralizing Abs, and induce catabody and irreversible Abs with enhanced target destruction capacity. Lead catabody medicines are ready for development.
Conflict of interest: The authors hold equity stakes in Covalent Bioscience. The studies were funded in part by Covalent Bioscience, the National Institutes of Health, SENS Research Foundation and Abzyme Research Foundation.
