Ask the Expert - David Spiegel, Yale University; Synthetic Immunology

Version 18

    Research in the Spiegel Laboratory focuses in the area of “synthetic immunology,” in which chemical tools are applied to the development of novel strategies for controlling and/or creating human immunity. These studies require broad-based expertise at the interface of chemistry and biology, and have the potential to advance fundamental chemical biology while also enabling discovery of novel therapeutic agents. For example, a main ongoing focus of the group is the design, preparation, and evaluation of bifunctional molecules capable of redirecting endogenous antibodies to disease-relevant cells and tissues. These constructs, called antibody-recruiting small molecules (ARMs), have proven efficacious in disease models for both cancer and HIV. Other interests include the study of how non-enzymatic post-translational modifications of proteins can alter immune function, and the development of immunomodulatory organisms. Professor Spiegel and his laboratory have received various honors for their research, including the NIH Director’s New Innovator Award, an Alfred P. Sloan Foundation Fellowship, the Ellison Medical Foundation New Scholar Award, a Kavli Foundation Fellowship, the Bill and Melinda Gates Foundation Grand Challenges Explorations Award, and the Camille and Henry Dreyfus Foundation New Faculty Award.

     

     

    Which area in synthetic immunology do you think is rapidly progressing and would develop into a major frontier in the field? (from Matthaeus Getlik)

    Synthetic Immunology is an extremely broad field, which encompasses developments in disparate areas, including those classically defined as immunobiology, organic chemistry, clinical medicine, and many others.  While it’s difficult to predict the impact that different research directions are likely to have in the long term, the scientific literature has seen significant recent activity toward the development of synthetic vaccines and cellular immunotherapies, especially those targeting cancer.  For example, recent successes in the synthesis of cancer-relevant carbohydrate antigens and elucidation of mechanisms to increase their immunogenicity are particularly encouraging.  Furthermore, “synthetic” approaches to modulating the function of antigen-presenting cells, such as targeted antigen delivery ex vivo priming strategies have also proven extremely exciting.  The FDA’s approval of Provenge (sipeulcel-T) has set an important precedent in this area.  Only time will tell which of these strategies emerges as particularly useful clinically, but at this point, they are all certainly quite exciting.

     


    Do you think synthetic immunology can be easily translated into a clinical setting? (from Helena M. Buzin)

    Translating developments in basic science into clinical settings is never straightforward, but there are certainly strategies in the area of synthetic immunology that have demonstrated promise for treating patients.  These include synthetic vaccines and cellular immunotherapies (see answer to question above) along with certain “synthetic” materials such as bispecific antibodies (including diabodies, BiTE constructs and others) – rationally designed proteins that bind disease-causing cells then directly interacting with and activate immune effector cells  – and antibody-recruiting molecules (ARMs) – bifunctional molecules that recruit hijack endogenous antibodies to disease-causing cells and particles (see review in ACS Chemical Biology, 2012, 1139–1151). Much of the research interest in this field is focused ultimately on either understanding or treating human disease processes.  My prediction is that new synthetic approaches for modulating immune function will continue to grow in popularity and impact during the upcoming years. 

     

    Is it possible to use your ARM strategy in which small molecule binds allosterically to recruit endogenous antibodies to disease cells? If you have already addressed that questions, can you please provide with references? (from Bishwajit Paul)

    The idea of targeting a disease-associated cell surface protein at an allosteric site using antibody-recruiting molecules is a good one. Assuming we define an allosteric site as one other than the “active site” at which ligand binding alters protein function, to my knowledge, such an antibody-recruiting molecule has not yet been reported.  The vast majority of ARM strategies have focused on targeting enzyme active sites (i.e., ARMs targeting prostate-specific membrane antigen) or ligand binding sites (i.e., ARMs that bind integrins, folate receptor, VEGF, urokinase receptor, gp120, and others – for a more complete discussion of published ARM strategies, please see the recent review in ACS Chemical Biology, 2012, 1139–1151).  That being said, an allosteric ARM could have certain benefits.  For example, target binding would not easily be competed under conditions of excess ligand/substrate.  If this is something that you are thinking about trying, I would certainly encourage it! 

     

    Chemical Biology is a multi-faceted field. For me it is like CHEMICAL biology or chemical BIOLOGY. As a chemists (myself being one), which skills set do we need to develop to ask more biologically pertinent questions? (from Bishwajit Paul)

    This is an extremely insightful question that is difficult to answer simply.  My opinion (and please be aware that this is only an opinion), is that the most important skillset for chemical biologists to develop is the ability to collaborate effectively.  No single researcher, or research group, can easily master the diverse range of areas comprising the entirety of “chemical biology.”  Developing collaborations – along with mechanisms for encouraging collaboration – between synthetic chemists, immunologists, cellular and vertebrate biologists, and clinicians will be essential for the continued growth of the field of Chemical biology, especially as researchers aim to define and answer questions of cutting-edge biomedical relevance.

     

    Presently, how prevalent is the development of antibody-based drugs?

    I think it's fair to say that we are currently experiencing a revolution in the growth of antibody-based drugs.  Between 2004 and 2008, the market for drugs derived from monoclonal antibodies (mAbs) has increased 5-fold, a rate of growth unmatched by any other drug class. Virtually every major pharmaceutical company now has multiple mAbs in their development pipeline; 31 agents are currently approved for clinical use and more than 300 are undergoing clinical trials.

     

    What are the major advantages and limitations of antibody-based therapeutics?

    Antibody-based drugs have provided a broad new series of options for both doctors and patients.  High-affinity, selective mAbs can be generated rapidly and easily against virtually any surface-exposed disease-relevant target. Furthermore, their ability to function through diverse mechanisms of action: including competing with ligands for mitogenic receptor sites, targeting cytotoxic agents to disease-associated tissues, and engaging immune effector mechanisms in clearing pathological cells or viruses.  These agents have therefore been able to render previously refractory targets now "druggable."  Of course, these agents are subject to certain limitations, primarily relating to their large molecular weights, and peptidic structures, including a potential for inducing life-threatening allergic reactions, lack of oral bioavailability, thermal instability, and high cost.

     

    Could you provide references to seminal work that demonstrated the utility of altering the antibody response to non-immunogenic targets on cell surfaces as a viable therapeutic option?

    A number of developments were important en route to the modern arsenal of immunotherapeutics.  Perhaps the most important of these was Jenner's discovery that immunization with vaccinia virus could induce immunity against the smallpox virus in the late 1700s.  Even though virtually nothing was known at the time about how these agents functioned, this strategy made clear that immunity could be induced against non-immunogenic pathogens, and lead to great health benefits.  Later, toward the end of the 19th century, it was realized that passive administration of antibodies specific for bacteria and microbial toxins could be protective in humans, and this led to Emil von Behring receiving the Nobel prize in 1901.  More recently, the development of hybridoma technologies for producing monoclonal antibodies in the 1970s by
    Kohler and Milstein, along with the demonstration that an anti-CD3 mAb (Muromonab-CD3) could be useful for prophylaxis against allogeneic transplant rejection in the 1980s, were highly enabling in demonstrating the therapeutic viability of these agents.   Finally, the commercial success of Remicade, Rituxan, Avastin, Herceptin, and Humira in the early 2000s should not be overlooked as encouragement for drug developers to enter the mAb arena over the past few years.

     

    What are some of the non-antibody-based immunotherapeutic strategies that have emerged recently and how do these work?

    In addition to mAb-based therapeutics, technologies that harness the human immune system in preventing and/or treating human disease have also experienced rapid growth in recent years. Treatment strategies involving administration of cytokines, DNA vaccines, and even cell-based immunotherapies have been developed for treating illnesses ranging from cancer to infectious disease.  For example, Dendreon corporation has recently obtained approval for Provenge, an autologous cellular immunotherapy shown to prolong life-span in patients with hormone-refractory prostate cancer.  The ongoing expansion in basic scientific knowledge about immune function are likely to lead to even more exciting developments in the near future.