Acute and subacute toxicity of chemotactic conjugates between monoclonal antibody and fMet-Leu-Phe in humans: A phase I clinical trial
Conjugates of the chemotactic peptide fMet-Leu-Phe (fMLP) to IgG retain chemotactic and antigen recognition function in vitro and enhance intra-tumour macrophage numbers in a guinea pig model. We report a study approved by the ethics committee on the acute toxicity of fMLP conjugates in ten consenting cancer patients with metastasizing melanoma and colon cancer. They were given increasing single doses (1–2500 µg) IgG-fMLP made with the anti-melanoma monoclonal antibody (mAb) 9.2.27. Clinical examinations and blood cell counts, urinalysis, electrolytes, and liver and kidney function tests before and after the infusion and weekly thereafter revealed no relevant toxicities. One patient had a herpes zooster exacerbation on day 1, which was judged to be coincidental. Peak post-infusion conjugate serum concentrations fell to unmeasurable levels within a few days. In no case was a human humoral anti-(mouse Ig) immune response detected.
Key wordsMonoclonal antibodies Melanoma Chemotactic peptide
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- 1.Bast RC Jr, Zbar B, Borsos T, Rapp HJ (1974) BCG and cancer. N Engl J Med 290: 1413–1420, 1458–1469Google Scholar
- 2.Bumol TF, Reisfeld RA (1982) Unique glycoprotein proteoglycan complex defined by monoclonal antibody on human melanoma cells. Proc Natl Acad Sci USA 89: 1245–1249Google Scholar
- 3.Byers VS, Baldwin RW (1988) therapeutic strategies with monoclonal antibodies and immunoconjugates. Immunology 65: 329–335Google Scholar
- 4.Durrant LG, Byers VS, Scannon PJ et al. (1989) Humoral immune responses to XMMCO-791-RTA immunotoxin in colorectal cancer patients. Clin Exp Immunol 75: 258–264Google Scholar
- 5.Hook WA, Schiffmann E et al. (1976) Histamine release by chemotactic formyl-methionyl-containing peptides. J Immunol 117: 594–596Google Scholar
- 6.Klimpel GR, Henney CS (1978) BCG induced suppressor cells: I. Demonstration of a macrophage-like suppressor cell that inhibits cytotoxic T cell generation in vitro. J Immunol 120: 563–569Google Scholar
- 7.Obrist R, Sandberg AL (1982) In vitro effect of antitumor antibody-chemotactic factor complexes. Clin Immunol Immunopathol 25: 91–102Google Scholar
- 8.Obrist R, Sandberg AL (1983) Enhancement of macrophage invasion of tumors by administration of chemotactic factor anti-tumor antibody conjugates. Cell Immunol 84: 169–174Google Scholar
- 9.Obrist R, Reilly R, Leavitt T, Knapp RC, Bast RC Jr (1983) Monocyte chemotaxis mediated by formyl-methionyl-leucyl-phenylalanine conjugated with monoclonal antibodies against human ovarian carcinoma. Int J Immunopharmacol 5: 307–314Google Scholar
- 10.Oldham RK, Foon KA, Morgan AC et al. (1984) Monoclonal antibody therapy of malignant melanoma: in vivo localisation in cutaneous metastasis after intravenous administration. J Clin Oncol 2: 1235–1244Google Scholar
- 11.Rosenberg SA, Lotze MT, Muul LM et al. (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Cancer 313: 1485–1492Google Scholar