Replies to post #3690 on ImClone Systems Inc (formerly IMCL)

[jbog]

bio, I found this April aacr presentation interesting.






The initial aim of targeted therapy was to achieve anticancer effects comparable to cytotoxic therapies, with more limited toxicity to normal tissue. Combining targeted therapies currently offers the best chance of achieving this goal.

Here we have compared the efficacy of a combination of IgG1 monoclonal antibodies targeting EGFR (cetuximab) and VEGFR2 (DC101) to a maximum tolerated dose (MTD) of standard chemotherapeutic combination used in the clinic. Cetuximab+DC101 was compared to Irinotecan/5-FU/Leucovorin (IFL) and 5-FU/Leucovorin/oxaliplatin (FOLFOX) in 5 subcutaneous xenograft models of colon cancer. The combination targeted therapy approach had greater efficacy than FOLFOX and IFL in the DLD-1 and HCT-8 models, and very similar efficacy in the GEO and HCT-116 model. In the KM-12 model, cetuximab+DC101 matched the efficacy of FOLFOX but was less efficacious than IFL. In an orthotopic model where luciferase expressing HT-29 cells were injected into the rectal lining, cetuximab+DC101 matched the ability of FOLFOX and IFL to inhibit primary tumor growth and lymph node metastasis.

Cetuximab+DC101 was also compared to MTD gemcitabine in 3 subcutaneous xenograft models of pancreatic cancer. The combination targeted therapy approach achieved significantly greater efficacy than gemcitabine in the BxPC-3 model, and similar efficacy in the HPAC and Mia Paca-2 models. In an orthotopic model in which luciferase expressing L3.7Pl cells were injected into the tail of the pancreas, cetuximab+DC101 achieved greater inhibition than gemcitabine in terms of primary tumor growth inhibition and a trend for reduction in liver metastasis. Thus combination targeted therapy with VEGFR2 and EGFR monoclonal antibodies has the potential to reduce the use of more toxic cancer treatments while still maintaining maximal therapeutic benefits.

[jbog]

Biophud,

It's looks like they took the IgG2 route.....


Combination Therapy Enhances the Inhibition of Tumor Growth with the Fully Human Anti–Type 1 Insulin-Like Growth Factor Receptor Monoclonal Antibody CP-751,871
Bruce D. Cohen, Deborah A. Baker, Catherine Soderstrom, George Tkalcevic, Ann Marie Rossi, Penny E. Miller, Mark W. Tengowski, Faye Wang, Antonio Gualberto, Jean S. Beebe and James D. Moyer
Pfizer Global Research and Development, Inc., Groton, Connecticut


Purpose: The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor.

Experimental Design: By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (Kd = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties.

Results: This antibody blocks binding of IGF-1 to its receptor (IC50 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC50 0.42 nmol/L) and induced the down-regulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L.

Conclusion: These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.


Key Words: IGF-1R • Antibody • Therapy • Biomarker