Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer

Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520-8107, USA.
Journal of the American Chemical Society (Impact Factor: 11.44). 11/2009; 131(47):17090-2. DOI: 10.1021/ja906844e
Source: PubMed

ABSTRACT Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biological evaluation of a class of bifunctional small molecules called antibody-recruiting molecules targeting prostate cancer (ARM-Ps) that enhance the recognition of prostate cancer cells by the human immune system. ARM-P derivatives were designed rationally via the computational analysis of crystallographic data, and we demonstrate here that these materials are able to (1) bind prostate-specific membrane antigen (PSMA) with high affinity (high pM to low nM), (2) template the formation of ternary complexes of anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, and (3) mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells. This manuscript describes the application of fundamental chemical principles to the design of a novel class of molecules with high therapeutic potential. We believe that this general small-molecule-based strategy could give rise to novel directions in treating cancer and other diseases.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cell interior is a complex and demanding environment. An incredible variety of molecules jockey to identify the correct position – the specific interactions that promote biology, which are often hidden among countless unproductive options. Ensuring that the business of the cell is successful requires sophisticated mechanisms to impose temporal and spatial specificity – both on transient interactions and their eventual outcomes. Two strategies employed to regulate macromolecular interactions in a cellular context are colocalization and compartmentalization. Macromolecular interactions can be promoted and specified by localizing the partners within the same subcellular compartment, or by holding them in proximity through covalent or non-covalent interactions with proteins, lipids, or DNA – themes that are familiar to any biologist. The net result of these strategies is an increase in effective molarity: the local concentration of a reactive molecule near its reaction partners. We will focus on this general mechanism, employed by nature and adapted in the lab, which allows delicate control in complex environments: the power of proximity to accelerate, guide, or otherwise influence the reactivity of signaling proteins and the information that they encode.
    Israel Journal of Chemistry (Online) 08/2013; 53(8). DOI:10.1002/ijch.201300063 · 2.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The healthy immune repertoire contains a fraction of antibodies that bind to various biologically relevant cofactors, including heme. Interaction of heme with some antibodies results in induction of new antigen-binding specificities and acquisition of binding polyreactivity. In vivo, extracellular heme is released as a result of hemolysis or tissue damage, hence the post-translational acquisition of novel antigen specificities might play an important role in the diversification of the immunoglobulin repertoire and host defense. Here, we demonstrate that seronegative immune repertoires contain antibodies that gain reactivity to HIV-1 gp120 upon exposure to heme. Furthermore, a panel of human recombinant antibodies was cloned from different B-cell subpopulations and the prevalence of antibodies with cofactor-induced specificity for gp120 determined. Our data reveal that upon exposure to heme, approximately 24% of antibodies acquired binding specificity for divergent strains of HIV-1 gp120. Sequence analyses reveal that heme-sensitive antibodies do not differ in their repertoire of variable region genes and in most of the molecular features of their antigen-binding sites, from antibodies that do not change their antigen-binding specificity. However, antibodies with cofactor-induced gp120 specificity possess significantly lower numbers of somatic mutations in their variable-region genes. This study contributes to the understanding of the significance of cofactor-binding antibodies in immunoglobulin repertoires and of the influence that the tissue microenvironment might have in shaping adaptive immune responses. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 01/2015; DOI:10.1074/jbc.M114.618124 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ability to monitor and manipulate antigen-specific immune responses would have a major impact on several areas of biology and medicine. In this perspective, I consider pharmacological methods to do this, with a focus on the development of abiological "antigen surrogates" capable of binding to the antigen-binding sites of antibodies and B cell receptors with high affinity and selectivity. I describe the application of combinatorial library screening to identify antigen surrogates for monoclonal antibodies of therapeutic interest using chronic lymphocytic leukemia as an example. Furthermore, I discuss the use of multiplexed assays for the quantification of antigen surrogate-antibody complexes as diagnostic tools and antigen surrogate discovery via serum screening. Although antigen surrogates are a fairly new concept, I argue that they will open new avenues for both basic and clinical research and that major advances can be expected over the next few years.
    Chemistry & Biology 09/2014; 21(9):1066-1074. DOI:10.1016/j.chembiol.2014.07.009 · 6.59 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014