The glycotope-specific RAV12 monoclonal antibody induces oncosis in vitro and has antitumor activity against gastrointestinal adenocarcinoma tumor xenografts in vivo

Abstract

RAV12 is a chimeric antibody that recognizes an N-linked carbohydrate antigen (RAAG12) strongly expressed on multiple solid organ cancers. More than 90% of tumors of colorectal, gastric, and pancreatic origin express RAAG12, and a majority of these tumors exhibit uniform RAAG12 expression. RAV12 exhibits potent cytotoxic activity in vitro against COLO 205 colon tumor cells via an oncotic cell death mechanism. RAV12-treated COLO 205 cells undergo morphologic changes consistent with oncosis, including cytoskeletal rearrangement, rapid plasma membrane swelling, and cell lysis. RAV12 inhibited the growth of RAAG12-expressing gastrointestinal tumor xenografts in athymic mice. In the case of SNU-16 tumor cells, twice weekly treatment of established s.c. tumors with 10 mg/kg RAV12 caused a f70% suppression of tumor growth at the end of the study. This preclinical data has led to the initiation of a phase I/IIA clinical study of RAV12 in patients with metastatic or recurrent adenocarcinoma. [Mol Cancer Ther 2007;6(3):856 -65]

A Novel Monoclonal Antibody Induces Cancer Cell Apoptosis and Enhances the Activity of Chemotherapeutic Drugs

“…A number of recently developed mAbs can kill target cells by a mechanism called oncosis (Loo et al, 2007;Zhang et al, 2010;Hernandez et al, 2011). Oncosis, as a mechanism of killing, requires a far higher concentration of mAb than is typi¬cally required for ADCC and CDC.…”

Lonely killers

“…47 RAV12 is a chimeric antibody that recognizes the N-linked carbohydrate antigen RAAG12. 48,49 It was constructed from the mouse mAb KID3. Both antibody versions induced membrane rupture upon binding to a colon tumor cell line.…”

“…Both antibody versions induced membrane rupture upon binding to a colon tumor cell line. 48 RAV12 was evaluated in a Phase 1 clinical study of patients with recurrent adenocarcinoma. 50 An IgM mAb that recognizes human embryonic stem cells, specifically through the podocalyxin-like protein-1, was found to be directly cytotoxic to these cells.…”

“…66 For KID3/RAV12, it was demonstrated that sodium influx was necessary for cell killing. 48 No data are available for the anti-Porimin mAb. 46,47 In summary, there are similarities in the killing mechanism exerted by the above described mAbs (Table 1); nevertheless, the relative contribution for this activity of both the antibody isotype and the nature of the antigen recognized on the target cells is not fully elucidated.…”

Anticorps et tumeurs solides

“…Ils peuvent être divisés en deux groupes : ceux qui, en plus de leurs effets directs, vont activer des fonctions immunes. Il s'agit d'anticorps d'isotype IgG1 capables d'induire l'ADCC (cytotoxicité cellulaire dépendante d'anticorps) ou la CDC (cytotoxicité dépendante du complément) (➜) tels que le MK-0646 (aussi dénommé h7C10 ou F50035) [26], IMC-A12 [27], R1507 [28], AMG 479 [29] ou RAV12 [30] ou SCH 717454 [31]. Un second groupe d'anticorps dépourvus de fonctions effectrices comme le BIIB022 (IgG4) [32] ou possédant des fonctions effectrices réduites comme le CP-751,871 (IgG2) [33] est également évalué.…”