• 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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Developing New Therapeutic Approaches to Human Disease: Targeting HIV-1 and Cancer


The major focus and driving vision of our laboratory concerns learning nature's strategies or improving upon them to develop new therapeutic approaches to human diseases through studies at the interface of synthetic organic chemistry, molecular biology, and medicine. Key accomplishments pioneered by us and our colleagues include the development of the first human and synthetic antibody phage libraries, the development of the first artificial transcription factors capable of regulating endogenous genes, and chemically programmed antibodies. Each of these approaches, first developed in this laboratory, has resulted in a new drug class that is currently in clinical trials for the treatment of a variety of diseases and in some cases validated with approved drugs created using these approaches. Several antibody drugs created using our methods are now approved drugs and many new antibody drugs are advancing in clinical studies. Sangamo Biosciences Inc. is advancing our zinc finger transcription factors in several clinical trials through a license to our patents in this area. CovX Inc., of which Professor Barbas is the founder, is advancing chemically programmed antibodies in clinical trials as well.

Therapeutic Antibodies

Our laboratory developed the first human antibody phage display libraries, as well as, the first synthetic antibodies and methods for the in vitro evolution of antibody affinity. The ability to manipulate large libraries of human antibodies and to evolve them in the laboratory provides tremendous opportunities to develop new medicines. Laboratories and pharmaceutical companies around the world now apply the phage display technology that we developed for antibody Fab fragments. In the laboratory, our focus has been in targeting cancer and HIV disease. One of our antibodies, IgG1-b12, has demonstrated efficacy in the protection of animals from primary HIV-1 virus challenge and has been further studied by many laboratories. We improved this antibody by developing in vitroevolution strategies that have significantly enhanced the neutralization activity of this antibody. By coupling laboratory-evolved antibodies with potent toxins, we have demonstrated that immunotoxins can effectively kill infected cells.

We are also developing genetic methods to halt HIV by gene therapy. Can antibodies be used to genetically modify human cells to make them resist HIV and perhaps develop a gene therapy approach towards protection against HIV? Yes. We have developed unique human antibodies that can be expressed inside cells to do just this. In the future, these antibodies might be delivered to the stem cells of HIV-1 infected individuals, allowing them to develop a disease free immune system and freeing them from the intense regimen of anti-viral drugs now required to treat this disease.

Extending our therapeutic efforts in the area of cancer, and founded in our increased understanding of antibody-antigen interactions, we have developed rapid methods for creating human antibodies from antibodies derived from other species. We have produced human antibodies that should provide for the selective starvation of a variety of cancers by inhibiting angiogenesis, as well as, antibodies that will be used to deliver radioisotopes to colon cancers to provide for their destruction. We hope to see some of these antibodies enter clinical trials with our collaborators at Sloan-Kettering in the next few years. Based on our studies in HIV-1, we have applied intracellular expression of antibodies directed against angiogenic receptors to create a new gene-based approach to cancer. Our studies indicate that this type of gene therapy might be successfully applied to the treatment of cancer. In order to realize this dream and other gene-based therapies, we are now developing new approaches to enable safe and effective gene delivery.

 

Therapeutic Applications of Catalytic Antibodies

The development of highly efficient catalytic antibodies opens the door to many practical applications, one of the most fascinating of which is their application in human therapy. We believe this strategy has the potential to improve chemotherapeutic approaches to diseases like cancer and AIDS. Chemotherapeutic regimes are typically limited by nonspecific toxicity. To address this problem, we have developed a novel and broadly applicable drug masking chemistry that operates in conjunction with our unique broad scope catalytic antibodies. This masking chemistry is applicable to a wide range of drugs since it is compatible with virtually any heteroatom. We have demonstrated that generic drug masking groups may be selectively removed by sequential retro-aldol-retro-Michael reactions catalyzed by antibody 38C2 (see the Catalytic Antibodies section of this website). This reaction cascade is not catalyzed by any known natural enzyme. Application of this masking chemistry to the anticancer drugs doxorubicin, camptothecin, and etoposide produced prodrugs with substantially reduced toxicity. These prodrugs are selectively unmasked by the catalytic antibody when it is applied at therapeutically relevant concentrations. The efficacy of this approach has been demonstrated in in vivo models of cancer. Currently we are developing more potent drugs, as well as, novel antibodies that will allow us to target breast, colon, and prostate cancer, as well as, HIV-1 infected cells. Based on our preliminary findings, we believe that our approach has the potential to become a key tool in selective chemotherapeutic strategies. To see a movie illustrating this approach, see our antibody/prodrug movie.

Chemically Programmed Antibodies

Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we developed a conceptually new device that equips small synthetic molecules with both immunological effector functions and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin αvβ3 and αvand β5 targeting RGD peptidomimetic and the reactive lysine of aldolase antibody 38C2 (see below). The resulting complex was shown to (i) spontaneously assemble in vitro and in vivo, (ii) selectively retarget antibody 38C2 to the surface of cells expressing integrins αvβ3 and αvβ5, (iii) dramatically increase the circulatory half-life of the RGD peptidomimetic, (iv) effectively reduce tumor growth in animal models of human Kaposi's sarcoma, colon cancer, and melanoma. By use of a generic antibody molecule that self-assembles into a covalent complex, many compounds can be turned into immunotherapeutic agents, thereby, not only increasing the diversity space that can be accessed but also multiplying the therapeutic effect. Novel drugs created using this approach are being advanced in clinical trials by CovX, Inc. See the Chemically Programmed Antibodies section of our website.

Zinc Finger Gene Switches and Enzymes

The solutions to many diseases might be found by simply turning genes on or off in a selective way or adding or deleting genes. In order to do this, we study molecular recognition of DNA by zinc finger proteins and study methods of creating novel zinc-finger DNA binding proteins. We have shown that it is possible to select or design proteins containing zinc fingers that recognize novel DNA sequences. These studies are aiding the elucidation of rules for sequence-specific recognition within this family of proteins. Towards this end, we have made significant progress in selecting and designing specific zinc finger domains that will constitute an alphabet of 64 domains that will allow any DNA sequence to be bound selectively. The prospects for this "second genetic code" are fascinating and promise a major impact on basic and applied biology. We have demonstrated the potential of this approach in multiple mammalian and plant cell lines, as well as, whole organisms. With characterized modular zinc finger domains, polydactyl proteins capable of recognizing an 18-nucleotide site are rapidly constructed. Our results suggest that zinc-finger proteins can potentially be used as genetic regulators for a variety of human aliments providing the basis for a new gene therapy strategy. The goal of this work is to develop this class of therapeutic proteins to inhibit or enhance the synthesis of proteins providing a direct strategy for fighting diseases of either somatic or viral origin. We are developing proteins that will inhibit the growth of tumors and others that will inhibit the expression of a protein known as CCR5, which is a key to infection of human cells by HIV type 1. We have reported the development of an HIV-1 targeting transcription factor that strongly suppresses HIV-1 replication and others that up-regulate fetal hemoglobin as a treatment strategy for sickle cell anemia. More recently, our efforts have focused on evolving zinc finger enzymes that modify the genome. These studies have led to the development of programmable zinc finger recombinases that promise -we hope!- to reshape the way scientists manipulate the genome for study and therapy of disease See the Polydactyl Zinc Finger and ZF Tools sections of this website.


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