A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma.

Abstract

PURPOSE:

To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II-driven dendritic cell activation.

EXPERIMENTAL DESIGN:

Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human anti-IMP321 antibody formation, and determine long-lived CD8 T cell responses.

RESULTS:

Twenty-one advanced renal cell carcinoma patients received 119 injections of IMP321 at doses ranging from 0.050 to 30 mg/injection s.c. biweekly for 6 injections. No clinically significant adverse events were observed. Good systemic exposure to the product was obtained following s.c. injections of doses above 6 mg. IMP321 induced both sustained CD8 T-cell activation and an increase in the percentage of long-lived effector-memory CD8 T cells in all patients at doses above 6 mg. Tumor growth was reduced and progression-free survival was better in those patients receiving higher doses (>6 mg) of IMP321: 7 of 8 evaluable patients treated at the higher doses experienced stable disease at 3 months compared with only 3 of 11 in the lower dose group (P = 0.015).

CONCLUSION:

The absence of toxicity and the demonstration of activity at doses above 6 mg warrant further disease-directed studies of IMP321 in combined regimens (e.g., chemoimmunotherapy).

• Authors: Chrystelle Brignone, Bernard Escudier, Caroline Grygar, Manon Marcu, Frédéric Triebel
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 19 Pg. 6225-31 (Oct 01 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19755389 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Antigens, CD
• Antineoplastic Agents
• HLA-D Antigens
• Recombinant Fusion Proteins
• Lymphocyte Activation Gene 3 Protein

Topics

• Animals
• Antigens, CD (adverse effects, metabolism, therapeutic use)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Carcinoma, Renal Cell (immunology, metabolism, pathology, therapy)
• Drug Administration Schedule
• Drug Evaluation, Preclinical
• Genes, MHC Class II (immunology)
• HLA-D Antigens (immunology)
• Humans
• Immunotherapy (methods)
• Kidney Neoplasms (immunology, metabolism, pathology, therapy)
• Macaca fascicularis
• Maximum Tolerated Dose
• Neoplasm Staging
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Tumor Cells, Cultured
• Lymphocyte Activation Gene 3 Protein