Immunological effects of chimeric anti-GD3 monoclonal antibody KM871 in patients with metastatic melanoma.
We conducted an open label dose-escalation phase I trial of chimeric anti-GD3 mAb KM871 in patients with metastatic melanoma. Patients were entered into one of five dose levels (1, 5, 10, 20, and 40 mg/m2) and received three infusions of KM871 at 2-wk intervals. A metastatic melanoma site was biopsied at day 7-10. Pharmacokinetics, immune function, and mechanism of action of KM871 were analysed. A total of 17 patients were entered into the trial; 15 were evaluable. KM871 had a serum half-life (T1/2-beta) based on ELISA of 10.39 +/- 1.12 d (mean +/- SD). Trough levels >1.0 microg/mL KM871 at 2 wk postinfusion were seen with the 10 mg/m2 and higher dose levels. There were no significant changes in white blood cell subsets or serum complement levels during KM871 treatment. KM871 was stable in vivo and maintained binding affinity and complement-dependent cytotoxicity (CDC) function up to 2 wk postinfusion. No significant trends in CDC or antibody-dependent cellular-cytotoxicity (ADCC) activity in patients were observed during treatment. Analysis of tumour biopsies demonstrated a significant increase in CD4+ T cell infiltrates compared to control patient tumours (P = 0.010), and in patients with either stable disease (2 patients) or a clinical partial response (1 patient) at restaging, a significant increase in CD3 and CD4 infiltrates in tumour over nonresponding patients was observed. The favourable immune properties of KM871, combined with this preliminary clinical data, indicate that KM871 has potential for the treatment of metastatic melanoma.
Scott
Andrew M
AM
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Austin Hospital, Heidelberg, Victoria, 3084, Australia.
Liu
Zhanqi
Z
Murone
Carmel
C
Johns
Terrance G
TG
MacGregor
Duncan
D
Smyth
Fiona E
FE
Lee
Fook-Thean
FT
Cebon
Jonathan
J
Davis
Ian D
ID
Hopkins
Wendie
W
Mountain
Angela J
AJ
Rigopoulos
Angela
A
Hanai
Nobuo
N
Old
Lloyd J
LJ
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D003167:Complement Activation; D003165:Complement System Proteins / Q000032:analysis; D005434:Flow Cytometry; D005732:Gangliosides / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D007958:Leukocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005732:Gangliosides; D011993:Recombinant Fusion Proteins; C026226:ganglioside, GD3; D003165:Complement System Proteins; C505881:ecromeximab