Abstract
The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at −80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months.
Highlights
Pharmaceutical companies have taken a reinvigorated notice of therapeutic monoclonal antibodies in the past decade and this continues to be a burgeoning field of product investigation and development
Conjugation of a monoclonal antibodies (mAb) with a chelate required the development of a family of standard operating protocols (SOPs) using methods that would be used by the manufacturer for the larger scale of production required for clinical trials
Only two tests have indicated the possibility of product failure
Summary
Pharmaceutical companies have taken a reinvigorated notice of therapeutic monoclonal antibodies (mAb) in the past decade and this continues to be a burgeoning field of product investigation and development. A casual perusal of magazines or viewing of the evening news one may see an advertisement for a mAb-based drug treating diseases such as psoriasis, Crohn’s disease or rheumatoid arthritis. In 2014, of 41 new molecular entities and therapeutic biological products approved, 6 were mAb [1,2]. Recent approval by the Food and Drug Administration (FDA) of the first α-radiation drug, Xofigo (Bayer, NJ, USA), has been granted. This singular approval has prompted significant interest in targeted α-radiation therapies
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