• Carlos F. Barbas, III, Ph.D.

    Kellogg Professor and Chair in Molecular Biology
    The Skaggs Institute for Chemical Biology
    and the Departments of Chemistry and Cell & Molecular Biology

  •   The Scripps Research Institute
    10550 North Torrey Pines Rd.
    La Jolla, CA 92037

  • Carlos F. Barbas, III, Ph.D. 
    Roberta  Fuller, Sr. Res. Assistant 
    Thom  Gaj, Ph.D. 
    Jarlath  Garcia 
    Xianxing  Jiang, Ph.D. 
    Brian  Lamb, Ph.D. 
    Robyn  Leary, Ph.D. 
    Jia  Liu, Ph.D. 
  • Mishelle  McClanahan-Shinn 
    Pedro  Perdigão 
    Bianca  Romana 
    Jingjing  Song 
    Mark  Wallen 
    Wei  Zhang, Ph.D. 
    Michael  Zorniak, Ph.D. 
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Chemically Programmed Antibodies: Merging Erhlich's Two Magic Bullets into One


If you have a dream of developing a new therapeutic approach, you should see the 1940 Warner Brothers film entitled "Dr. Ehrlich's Magic Bullet". The film chronicles the life of Paul Erhlich and his development of both antibody therapeutics in serum therapy and the first targeted small molecule therapeutic, Salvarson or "606" for the treatment of syphilis. Everything from 'high-throughput' screening leading to the identification of compound number 606 as the lead molecule, to the tribulations of 'phase 4' studies and the realization that drugs can have unexpected side effects in certain individuals are recounted.

Since Ehrlich's recognition of the potential of antibodies as therapeutic agents in the early twentieth century, the development of monoclonal antibody (mAb) technology in the 1970s, and more recently the development of antibody phage libraries, mAbs have gained importance for the treatment of a variety of diseases. In addition to a dozen mAbs approved by the US Food and Drug Administration, a considerable number of biotechnology drugs in development are mAbs and recent IND applications for mAbs have eclipsed those filed for small molecules. The mounting success of the antibody molecule as a therapeutic agent is based on at least three properties; (i) an Fab moiety that permits antigen binding with high specificity and affinity, (ii) an Fc moiety that mediates effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), and (iii) a molecular weight of at least 150 kD that permits a circulatory half-life of up to 21 days. By contrast, conventional therapeutic agents based on small synthetic molecules and peptides are clearly limited with respect to their short half-life in circulation, particularly in chronic treatment regimens like those needed in cancer therapy, and their inability to mediate effector functions. Unlike therapeutic antibody development that faces limitations in terms of manufacturing due to bioreactor requirements, industry has proven itself capable of manufacturing a very large diversity of small molecule drugs in large-scale and most drugs are small molecules.

Our development of Chemically Programmed Antibodies is based on recognition of both the strengths and weaknesses of small molecule and antibody approaches and the development of an approach that creates new immunotherapeutics by drawing on the relative strengths of both. We suggest that a blend of the unlimited chemical diversity of small synthetic molecules with the longer serum half-life and the effector function of an antibody molecule will lead to therapeutic agents with superior properties. Inspired by Ehrlich, we aim to test this hypothesis with this new class of Magic Bullets.


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