Raven's lead therapeutic antibody, RAV12, is in Phase 1/2a development for the treatment of adenocarcinomas. Adenocarcinomas are malignant tumors of the epithelial cells that line glands or viscera. Between 90 and 100 percent of adenocarcinomas of gastrointestinal origin (e.g. colorectal, stomach, and pancreatic cancers) express the RAV12 defined antigen, RAAG12. Expression in these tumors is typically uniform and high. Raven selected RAV12 as a therapeutic candidate based on results of xenograft studies demonstrating potent cytotoxic activity against colon, gastric, and pancreatic tumors. Raven initiated clinical studies of RAV12 in patients with refractory adenocarcinomas particularly those arising in the gastrointestinal tract in 2004.

RAV12 Highlights:

• RAV12, is a chimeric (human/murine) monoclonal antibody of the IgG1 class, which is 89% identical to human antibodies. RAV12 was identified through Raven's discovery process by immunizing mice with a kidney progenitor cell line and producing hybridomas. Resulting antibodies were then screened to determine their degree of binding to tumor cells and relative lack of binding to normal tissues.
• Characterizations of RAV12 and its target have recently been published. RAAG12, the antigen target of RAV12 is a carbohydrate moiety whose expression is limited to primates. The structure of the RAV12 epitope is Galß 1-3GlcNacß 1-3Gal. Multiple RAV12 binding sites exist per sugar side-chain resulting in a very high apparent affinity and a nearly unmeasurable dissociation rate. Adenocarcinomas arising in breast, endometrial, ovarian, lung and prostate, display the RAA12 antigen to varying degrees. RAAG12 expression in normal tissues is generally limited to the apical membranes of certain epithelia of the GI track and the hepatobiliary system. Preclinical in vitro and in vivo experiments have suggested that RAV12 may have several anti-tumor activities, including direct cytotoxicity by a mechanism termed oncosis, antibody-dependent cellular cytotoxicity, complement mediated cytotoxicity, and alterations of cell survivability through down regulation of growth factor receptors. Oncosis is a form of cell death, distinct from apoptosis, that is characterized by loss of membrane integrity, followed by cell and organellar swelling, and death.
• RAV12 is highly efficacious in human colon, gastric, and pancreatic tumor xenograft models in vivo. The antibody was well tolerated in repeat dose, 5-week and 26-week, primate toxicology studies. No histopathological changes were observed in the extended study.
• Raven reported preliminary results from a Phase I/2a clinical trial of RAV12. An open-label, multi-dose, single-arm, dose escalation phase 1 study is underway in patients with recurrent adenocarcinomas of GI origin or other origin if proven to be RAAG12 expressing. The objectives of the trial are to define the safety profile of the antibody, to determine the maximally tolerated dose, to define the pharmacokinetics of the antibody in humans, to evaluate immunogenicity, and to describe, in preliminary fashion, efficacy. For more information on the clinical trial, please go to www.clinicaltrials.gov.
• As of April 15, 2007, 6 cohorts of patients constituting 33 patients have been enrolled in the Phase 1/2a clinical trial.
• Raven has a strong intellectual property position concerning the antigen target of RAV12, antibodies to that target, and their uses in cancer therapies.
• Sufficient GMP material has been produced for Phase 1 and Phase 2 clinical trials.

Additional Development Opportunities for RAV12:

Raven has identified several promising opportunities for Phase 2 development of RAV12 that may be pursued independently or in collaboration with a partner. These opportunities include monotherapy for refractory colorectal cancer and combination therapy with small molecule chemotherapeutics in other GI malignancies or malignancies arising outside the GI tract.

RAV12 is active in in vivo tumor xenograft models, blunting tumor growth as a single agent in both simultaneous treatment models and established tumor models, and synergizing with chemotherapy to prolong survival in a human pancreatic cell line xenograft (see Figure below).

RAV12 synergizes with Gemcitabine in tumor xenograft model