Abstract 4747: Redirecting the endogenous immune response against prostate cancer using an antibody-recruiting small molecule
Authors: Zhang Andrew X. , Hoimes Christopher J. , Murelli Ryan P. , Saltzman W. Mark , Spiegel David A. 
Published: August 2012

Abstract
Background: Prostate cancer is the second leading cause of cancer related deaths in American males in 2011. Immunotherapy has emerged as a method of treatment against androgen-independent prostate cancer, but its applicability is limited by its cost, difficulty of administration, and potential inherent immunogenicity. We have developed a class of antibody-recruiting small molecule targeting prostate cancer (ARM-P) capable of enhancing antibody-mediated immune recognition of prostate cancer cells. ARM-P targets the prostate specific membrane antigen (PSMA), a membrane bound protein overexpressed on many forms of prostate cancer, and simultaneously binds to anti-dinitrophenyl (DNP) antibodies present in the bloodstream. ARM-P-based treatment of prostate cancer confers the advantages of immunotherapy but also benefit from ease of synthesis and administration with no inherent immunogenicity. Methods: PSMA-positive LNCaP prostate xenografts were immunized using DNP-ficoll and treated with ARM-P (every other day), docetaxel (weekly), or the combination for 28 days, and tumor mass and survival were used as measures of efficacy. Negative controls included vehicle, LNCaP xenograft in the absence of immunization, and PSMA-negative DU145 xenografts. LNCaP cells and PSMA negative DU145 cells were used for in vitro assays on ARM-P. Specifically, antibody recruiting was measured using a fluorescently labeled anti-DNP antibody, and ARM-P mediated antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells was measured in a standard calcein release assay. Results: Prostate xenograft studies show that compared to vehicle, ARM-P inhibits growth of LNCaP tumors and prolongs survival in the presence of anti-DNP antibody (median survival of 55 days) with an efficacy comparable to that of docetaxel. Combination therapy of ARM-P and docetaxel showed an enhanced effect and improved median survival to 71 days. ARM-P showed no effect in the absence of DNP immunization and DU145 xenografts. To elucidate the mechanism of action of ARM-P, we showed that ARM-P recruits anti-DNP antibodies to LNCaP cells in a dose dependent fashion, and can be outcompeted by titrating in respective ligands for PSMA and anti-DNP antibody. We observed up to 40% cell killing mediated by ARM-P on LNCaP cells in ADCC assays with anti-DNP IgG and human immune effector cells. Cell death was not observed under identical conditions for DU145 cells and in the absence of effector cells. Conclusions: ARM-P is able to selectively enhance immune recognition and destruction of PSMA-expressing prostate cancer cells, and demonstrates in vivo efficacy at a level comparable to that of docetaxel. Taken together, ARM-P presents an example where a small molecule is capable of modulating an immune response in a manner similar to that of a biologic, while addressing many shortcomings of biologics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4747. doi:1538-7445.AM2012-4747