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Alpha-Emitting Bismuth Cyclohexylbenzyl DTPA Constructs of Recombinant Humanized Anti-CD33 Antibodies: Pharmacokinetics, Bioactivity, Toxicity and Chemistry

Memorial Sloan-Kettering Cancer Center, New York, NY
MAP Medical Technologies, Inc., Tikkakoski, Finland
Chemistry Section, National Cancer Institute, National Institutes of Health, Bethesda
Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland
Pharmactinium, Inc., Wilmington, Delaware
European Commission, Joint Research Center, Institute for Transuranium Elements, Karlsruhe, Germany

Correspondence: For correspondence and reprints contact: David A. Scheinberg, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

ABSTRACT

The -particle—emitting radionuclides have several physical characteristics that make them attractive candidates for radioimmunotherapy: (a) high linear energy transfer; (b) short path lengths (50–80 µm); and (c) limited ability of cells to repair damage to DNA. This article describes the pharmacokinetic, bioactivity, toxicity and chemical characteristics of -particle—emitting, ²¹³Bi and ²¹²Bi radiometal conjugated HuM195 (anti-CD33) constructs. Conjugation of HuM195 to SCN-CHX-A-DTPA resulted in the attachment of up to 10 chelating ligand molecules per antibody. Results: Radiolabeling efficiency of the CHX-A-DTPA-HuM195 construct with ²¹³Bi was 78% ± 10% (n = 46) after 10 min at specific activities of up to 1110 MBq/mg. The immunoreactivity of the ²¹³Bi-labeled CHX-A-DTPA-HuM195 construct was 84% ± 10% (n = 28) and was independent of the specific activity. The bismuth-labeled CHX-A-DTPA-HuM195 construct was rapidly internalized into the cell in a time-dependent manner ranging from 50% at 1 h to 65% at 24 h. ²⁰⁵Bi/²⁰⁶Bi-labeled constructs were stable for at least 2 d in vitro in the presence of human serum at 37°C. After injection into mice, there was no uptake or loss of bismuth to mouse tissues, which do not express CD33, or to the kidney, which has avidity for free bismuth. Mice injected intraperitoneally with doses of (²¹³Bi)CHX-A-DTPA-HuM195 ranging from 18.5 to 740 MBq/kg showed no toxicity, but at 2590 MBq/kg, two of the three mice died within 2 wk and a third mouse showed significant reductions in white blood cell counts. Mice injected intraveneously with doses of (²¹³Bi)CHX-A-DTPA-HuM195 up to 370 MBq/kg exhibited little toxicity, but 666 MBq/kg was above the MTD for mice. Leukemia cell killing in vitro with bismuth-labeled HuM195 showed dose- and specific activity-dependent killing of CD33+ HL60 cells; approximately 50% killing was observed when two bismuth atoms (50 fM radiolabeled antibody) were initially bound onto the target cell surface. Conclusion: Alpha-emitting antibodies are among the most potent cytotoxic agents known, yet are specific and appear safe in vivo. The physical and biochemical characteristics of the ²¹³Bi isotope and its generation, as well as the biochemistry of the ²¹³Bi-labeled CHX-A-DTPA-HuM195 construct, make it possible to use the constructs safely and feasibly in humans at therapeutic levels.

Key Words: Monoclonal antibodies • -particles • ²¹³Bi • ²¹²Bi • CHX-A-DTPA • HuM195 • M195

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