CBR96-doxorubicin immunoconjugate

cBR96-doxorubicin immunoconjugate (BMS-182248/SGN-15; also known as cBR96-Dox) is an antibody-drug conjugate or (ADC) directed to the Lewis-Y antigen designed for the treatment of cancer. The payload is the chemotherapy drug doxorubicin which is connected with a hydrazone linker to cysteine residues of the Lewis-Y specific (chimeric) monoclonal antibody BR96.^[1] Following internalization, the hydrazone is hydrolyzed within the acidic environment of target cell endosomes and lysosomes to release active cytotoxic drug.

Clinical Development

In clinical trials cBR96-Dox was found to be highly active in regressing large human tumor xenografts implanted in mice or rats.^[2][3] Multiple tumor models including lung, breast and colon were evaluated, and cBR96-Dox was found to have broad and potent anti-tumor activity, even in doxorubicin-resistant tumors.

A randomized 60-patient phase II study of cBR96-Dox in NSCLC patients who had failed front-line therapy was completer in 2004. Two-thirds of the patients received the combination of cBR96-Dox and Taxotere and one-third received Taxotere alone. In this study, patients on the combination arm received cBR96-Dox and Taxotere simultaneously. Final data from this study demonstrated that patients receiving cBR96-Dox in combination with Taxotere had a median overall survival of 7.3 months, compared to 5.9 months for patients receiving Taxotere alone. Predicted overall survival at one year and 18 months for patients receiving the combination therapy was 29 percent and 18 percent, respectively, compared to 24 percent and 8 percent, respectively, for patients receiving Taxotere alone.

While the randomized phase II study was ongoing, the Seattle Genetics generated additional preclinical data suggesting that dosing cBR96-Dox5 several days prior to Taxotere could improve the antitumor activity of the combination therapy. To evaluate the impact of dosing schedule on clinical efficacy, the company conducted two open label phase II studies of cBR96-Dox plus Taxotere in NSCLC patients who had failed front-line or front-line and second-line therapies. The trials were primarily designed to compare the uptake of a biomarker (FDG) as measured by positron emission tomography (PET) imaging in patients receiving cBR96-Dox plus Taxotere either simultaneously or sequentially. This approach was used to determine the relative activity of the two dose schedules on an expedited basis prior to obtaining a difference in patient survival.

One half of the patients in the PET trials received cBR96-Dox three days prior to Taxotere and the other half received the combination simultaneously. Fourteen patients have been treated in the U.S.-based study and 38 patients have been treated in a parallel study conducted in Russia. PET scans were analyzed by quantitative assessment of tumor standard update value (SUV) to measure metabolic activity of the primary tumor before and after treatment. Data from both studies suggest an advantage for patients receiving sequential dosing. In the U.S. study, of the first six evaluable patients, those receiving sequential dosing demonstrated an average decrease in SUV of 25 percent, compared to an average decrease of eight percent in patients receiving simultaneous dosing. In the Russian study, of 32 evaluable patients, those receiving sequential dosing demonstrated an average decrease in SUV of 32 percent, compared to 23 percent for patients receiving simultaneous dosing. The combination was well tolerated with both dosing schedules.

Although this data was encouraging, Seattle Genetics decided to discontinue development of this first-generation antibody-drug conjugate (ADC), to focus on advancing its other pipeline programs and second-generation ADC technology.^[4]

References