rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to
complement‐dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 • histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab mediated killing of CD20‐positive target cells in mice and non‐human primates. The presence of the tag, while allowing for easy purification by Ni‐NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His‐tag. In the present study we performed preclinical studies in two animal species with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++
dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as
a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an Investigational New Drug (IND) application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B‐cell malignancies.
|Journal||Molecular Therapy - Methods and Clinical Development|
|Publication status||Published - 30 Mar 2016|