Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models.
IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared with IL15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil, and monocyte counts by >8-fold. ALT-803 dose-dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4(+), and CD8(+) memory T-cell subsets. In vitro studies demonstrated ALT-803-mediated stimulation of mouse and human immune cell proliferation and IFNγ production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans.
Altor BioScience Corporation, Miramar, Florida.
Peter R
PR
Rhode
Altor BioScience Corporation, Miramar, Florida.
Jack O
JO
Egan
Altor BioScience Corporation, Miramar, Florida.
Wenxin
W
Xu
Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin.
Hao
H
Hong
Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
Gabriela M
GM
Webb
Altor BioScience Corporation, Miramar, Florida.
Xiaoyue
X
Chen
Altor BioScience Corporation, Miramar, Florida.
Bai
B
Liu
Altor BioScience Corporation, Miramar, Florida.
Xiaoyun
X
Zhu
Altor BioScience Corporation, Miramar, Florida.
Jinghai
J
Wen
Altor BioScience Corporation, Miramar, Florida.
Lijing
L
You
Altor BioScience Corporation, Miramar, Florida.
Lin
L
Kong
Altor BioScience Corporation, Miramar, Florida.
Ana C
AC
Edwards
Altor BioScience Corporation, Miramar, Florida.
Kaiping
K
Han
Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin.
Sixiang
S
Shi
Altor BioScience Corporation, Miramar, Florida.
Sarah
S
Alter
Vaccine & Gene Therapy Institute, Oregon Health & Science University, Portland, OR, USA.|Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
Jonah B
JB
Sacha
Altor BioScience Corporation, Miramar, Florida.
Emily K
EK
Jeng
Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin.
Weibo
W
Cai
Altor BioScience Corporation, Miramar, Florida.
Hing C
HC
Wong
D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007167:Immunotherapy; D019409:Interleukin-15 / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D008546:Melanoma, Experimental / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011506:Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D011993:Recombinant Fusion Proteins; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C582303:ALT-803; D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D016207:Cytokines; D019409:Interleukin-15; D011506:Proteins; D011993:Recombinant Fusion Proteins