Choosing the Right Dimension of Purity
Croda
Raven Biotechnologies have announced positive initial clinical trial results for their anticancer antibody that causes tumour cells to swell up and die.
The San Francisco-based firm has been testing RAV12 since December 2004. This latest data comes from a Phase I/IIa trial, which began in April this year in 33 patients with various gastrointestinal cancers, such as colorectal, stomach and pancreatic.
The part human, part rodent (murine) monoclonal antibody (MAb) targets a specific N-linked sugar structure called RAAG12, which is found on the surface of this type of tumour in primates. Over 90 percent of malignant tumours of the epithelial cells that line glands (adenocarcinomas) display this antigen and are therefore susceptible to attack by Raven's drug.
Having established the antibody is safe, these latest results will enable Raven to choose the most suitable dose of RAV12 to use in a Phase II trial. The main side-effects seen were infusion-associated abdominal discomfort and diarrhea, and elevated liver function tests. However, by giving the drug in small amounts until the required dose is reached, rather than in one amount, Raven hopes to alleviate these effects.
"A fractionated dosing regimen allows us to deliver RAV12 with an acceptable level of toxicity, while maintaining exposure that is associated with a tumour response," said Dr George Schreiner, CEO at the firm.
Antibodies that tackle cancer can exert their effects in a number of ways and Raven believes the fact that RAV12 can utilise multiple mechanisms is what sets it apart from these rivals. Whereas many cancer drugs cause tumour cells to enter a programmed cell death cycle called apoptosis, Raven's drug is directly cytotoxic to a human colon cancer cell lines through induction of 'oncotic' cell death. This is where the cell swells up and the membrane becomes more permeable. This, in turn, can cause the cell to change shape and volume, and for the cytoplasm to spill out into fluid filled blisters on the cell surface.
Secondly, the antibody can bind to RAAG12 and then to the Fc receptors on monocytes, macrophages, and natural killer cells, for example, causing the tumour cell to be killed via antibody-dependent cellular cytotoxicity (ADCC). Thirdly, the drug also mediates complement dependent cytotoxicity where the target cell membrane is punctured, which, in turn, causes cell lysis and death. Finally, Raven claims that the antibody alters cellular signalling required for cell survival.
The patients in the trial all had gastrointestinal adenocarcinomas or from another origin if the tumour still expressed the RAAG12 antigen.
"We are particularly encouraged to have seen a clinical response in one of the patients with advanced stage gastrointestinal cancer," said Schreiner.
The patient in question experienced a partial remission with time to progression exceeding eight months and one patient with advanced pancreatic cancer also had a greater than 50 per cent reduction in the tumour marker, CA19-9 and experienced disease stability for more than five months.
