Novel multivalent/multifunctional agents derived from a humanized anti-insulin-li

DESCRIPTION (provided by applicant): Cancer of the kidney and renal pelvis killed approximately 13,010 men and women in the United States last year. One of the most challenging forms of this type of cancer is metastatic renal cell carcinoma (RCC). It has resisted attempts of curative radiotherapy and chemotherapy. Current treatment regimens include cytokine therapy with IFN-a2b and PTK targeted therapies with anti-vascular endothelial growth factor (VEGF) receptor antibodies or mammalian target of rapamycin (mTOR) inhibitors, such as temsirolimus. These new treatments have had only modest effects on patient outcomes when used alone or in combination. Another target that has emerged is the insulin-like growth factor-I receptor (IGF-IR). It is expressed on a wide range of RCC types and its expression has been linked to a positive association for poor patient survival. In addition, anti-IGF-IR antibodies have been shown to have an additive effect when used in conjunction with mTOR inhibitors due to their ability to inhibit the Akt-signaling pathway in RCC cells. We have a humanized anti-IGF-IR antibody, hR1 that has undergone modification to allow us to attach either four hR1 Fabs or four IFN-a2b molecules to it. These new molecules are being developed as a new generation of agents specific for treating renal cell carcinomas by multivalent antibodies and immunocytokines. This was done via our dock-and-lock (DNL) platform technology in which the dimerization and docking domains (DDD) and anchoring domains (AD) involved with the natural association of the cAMP-dependent protein kinase and the A-kinase anchoring proteins are used to link the various components to hR1. The resulting hexavalent hR1 reagent (Hex-hR1) will be composed of hR1 IgG linked to four hR1 Fabs. Additionally, we can generate a bivalent hR1 IgG reagent with four IFN-a2b molecules attached to the Fc-portion of the IgG molecule (1R-2b). Using Hex-hR1 and 1R- 2b agents in combination with an mTOR inhibitor (temsirolimus) we will take advantage of the additive effect seen when mTOR inhibitors are combined with an anti-IGF-IR antibody. Past experience with a hexavalent anti-CD20 agent (Hex-hA20) and an anti-CD20-IFN-a2b agent (20-2b) demonstrated superiority in comparison to either the parental antibody or a non-targeting IFN-a2b agent. We expect that Hex-hR1 will likewise be superior to hR1 when combined with chemotherapy and that targeting IFN-a2b to RCC will also result in significantly improved efficacy over that of a non-targeting IFN-a2b agent. We will test these interactions in vitro against a panel of RCC cell lines studying possible synergy or additive effects. Additionally, mice bearing s.c. RCC tumors will undergo efficacy experiments to determine if the effects seen in vitro translate to the in vivo setting. PUBLIC HEALTH RELEVANCE: Two new molecules are being developed as a new generation of agents specific for treating metastatic renal cell carcinomas by multivalent antibodies and immunocytokines. This was done via our dock-and-lock (DNL) platform technology in which the dimerization and docking domains (DDD) and anchoring domains (AD) involved with the natural association of the cAMP-dependent protein kinase and the Akinase anchoring proteins are used to link the various components to an anti-IGF-IR monoclonal antibody.