CLINICAL EFFECTS OF HUMAN MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA MIP-1-ALPHA (LD78) ADMINISTRATION TO HUMANS - A PHASE-I STUDY IN CANCER-PATIENTS AND NORMAL HEALTHY-VOLUNTEERS WITH THE GENETICALLY-ENGINEERED VARIANT, BB-10010

BB(-)10010 is a genetically engineered variant of human macrophage inf lammatory protein-1 alpha (hMIP-1 alpha) with improved pharmaceutical formulation properties. Although initially described as a pro-inflamma tory cytokine, it is now recognised that hMIP-1 alpha has additional e ffects on haemopoietic stem cell cycling and on human immunodeficiency virus uptake by macrophages. In view of the potential clinical utilit y of the molecule, we have embarked on a clinical trials programme to evaluate the safety, tolerability and haematological effects of BB-100 10. We now report the results of two phase I clinical studies in which 49 subjects (9 patients with advanced breast carcinoma and 40 normal healthy volunteers) received escalating doses of BB-10010, from 0.1 to 300 mu g/kg using the subcutaneous (s.c.) or intravenous route (i.v.) of administration. Treatment was associated with a dose-related incre ase in monocyte count which peaked at 200% of steady-state levels and was preceded by an acute, short-lived, monocytopenia, 50-100% of basel ine. No measurable effects were noted on other leucocyte subsets or on circulating progenitor cell numbers. In all cases, BB-10010 was extre mely well tolerated with no significant toxicity observed at any dose level and a maximum tolerated dose was not defined. Pharmacokinetic an alysis revealed that serum concentrations of BE-10010 were detectable using doses of greater than or equal to 10 mu g/kg i.v. or greater tha n or equal to 30 mu g/kg s.c., and that a single s.c. injection result ed in sustained plasma levels over a 24 h period. These preliminary st udies have confirmed the safety and tolerability of BE-10010 using a d ose range up to 300 mu g/kg. Further clinical studies are ongoing to d etermine the biological effects and to investigate the potential myelo protective properties using a variable dose range and schedule of BB10 010 in combination with cytotoxic chemotherapy. (C) 1998 Elsevier Scie nce Ltd. All rights reserved.