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


METHODS
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).


CONCLUSIONS
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).
Brignone
Chrystelle
C
Immutep SA Orsay, France.
Escudier
Bernard
B
Grygar
Caroline
C
Marcu
Manon
M
Triebel
Frédéric
F
D000818:Animals; D015703:Antigens, CD / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005802:Genes, MHC Class II / Q000276:immunology; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007680:Kidney Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008252:Macaca fascicularis; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000970:Antineoplastic Agents; D006681:HLA-D Antigens; D011993:Recombinant Fusion Proteins; D000093322:Lymphocyte Activation Gene 3 Protein