A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy

Abstract

BackgroundProstate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.MethodsBinding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of β-hexosaminidase from effector cells. In vivo degranulation was monitored in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells.ResultsThe anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and FcεRI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting.ConclusionsThe anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.

IgE immunotherapy

“…1). 8,20,21,[23][24][25][26][27]60,[140][141][142] Murine anti-gp36 IgE The first study performed with a tumor-targeted IgE antibody was conducted in the early 1990s. 23 A murine IgE specific for the major envelope glycoprotein (gp36) of the mouse mammary tumor virus (MMTV) was produced and its anti-cancer efficacy evaluated in immunocompetent mice bearing syngeneic MMTVpositive s.c tumors.…”

“…144 Mouse/human chimeric anti-PSA IgE Most recently, a mouse/human chimeric monoclonal IgE antibody raised against prostate-specific antigen (PSA), a prostate cancer-specific tumor associated antigen, has been engineered. 142 The murine IgG1 equivalent mAb AR47.47, specific for human PSA, has previously been shown to enhance antigen presentation by human DCs, and induce both CD4+ and CD8+ T cell activation when complexed with PSA. 145 In this study, the anti-PSA IgE, complexed with the PSA antigen, was capable of enhancing antigen presentation by human DCs in vitro, inducing CD4+ and CD8+ T cell activation.…”

“…Furthermore, no toxicities were reported during the previously-described in vivo studies of recombinant IgE antibodies targeting tumor-associated antigens, in which the Fc region of the therapeutic antibody was capable of cross-reacting with the animal's native Fcε receptors, or with co-administered PBMC. 8,20,21,[23][24][25][26][27]60,[140][141][142] Finally, a thorough in vitro study that examined the propensity of a tumor antigen-specific IgE to induce early events that could lead to Type I hypersensitivity was recently conducted. 148 Upon addition of MOv18 IgE to human sera or to whole human blood of patients or healthy volunteers, neither functional degranulation nor significant activation of human basophils were observed.…”

“…148 This study was replicated using a mouse/human chimeric monoclonal IgE antibody raised against PSA. 142 The engineered anti-PSA IgE antibody was capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, thereby suggesting that systemic administration of the antibody would be unlikely to trigger anaphylaxis. However, a thorough evaluation of toxicity in vivo is yet be conducted.…”

Role and Redirection of IgE against Cancer

“…[69]. (C) TAA-specific IgE mAbs for passive therapy [70][71][72][73][74][75][76][77][78][79][80]. (D) Same approach as in C with a potentiation provided by FcRI-engineered CTLs [81,82].…”