Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists

Abstract

The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.

A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

“…Mice received 1 mg/kg (20 mg/mouse) daily by IP injection, as was used in previous studies. 33 No toxicity was noted during therapy. Before its use in vivo, stock solutions of TKIs were prepared in dimethyl sulfoxide (DMSO), with the scheduled dose of TKI in 50 mL DMSO per mouse.…”

Respuestas tisulares y vasculares en retinopatía hipertensiva con anticuerpos monoclonales como terapia antiangiogénica

“…Las variables de estudio fueron fuga vascular asociada con los procesos de neovascularización, mejoría en AV y reducción de edema macular. Se revisaron para esta categoría varios estudios preclínicos de modelos de retinopatía hipertensiva y diabética con angiogénesis y cambios maculares en progreso, que muestran un 96,6 % de mejoría en estas variables ( Criswell, 2008;Hossein y Chader, 2007;Hu, Gale y Shields, 2012).…”

“…El 98,2 % de los participantes después de tres meses de tratamiento tuvo disminución de 133 µm en promedio del espesor macular central, con mejoría de AV en los pacientes tratados con anticuerpos monoclonales de más de tres líneas (Ashish Hu, Gale y Shields, 2012;Rodríguez, 2012;Vilaró, 2011).…”

“…Los procesos inflamatorios y proteolíticos como el VEGF continúan su curso. De ahí la importancia de utilizar anticuerpos monoclonales que son específicos para inhibir estos procesos moleculares (Hu, 2012). Los fármacos anti-VEGF actualmente disponibles incluyen macugen® (pegaptanib), lucentis® (ranibizumab), avastin® (bevacizumab), así como rituximab, daclizumab, efalizumab, alemtuzumab, infliximab y adalimumab.…”

Physiology and Pharmacology of Plerixafor

“…Furthermore, plerixafor was able to improve survival and decrease the leukemia burden when administered with cytosine arabinoside compared with chemotherapy alone [92]. Plerixafor was also able to enhance the response of the therapeutic antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) in a model of disseminated lymphoma [93]. In the latter instance, the therapeutic benefit was in part due to mobilization of neutrophils and enhancement of the antibody-dependent cellular cytotoxicity.…”