Pretargeted radioimmunotherapy of pancreatic cancer xenografts: TF10-90Y-IMP-288 alone and combined with gemcitabine.
Pancreatic cancer is a silent disease that most commonly presents in an already metastatic form. Current treatment options provide little survival benefit. Radiolabeled PAM4 IgG, a monoclonal antibody that recognizes a unique epitope associated with a mucin found almost exclusively in pancreatic cancer, has shown encouraging therapeutic effects in animal models and in early clinical testing ((90)Y-humanized PAM4 IgG, (90)Y-clivatuzumab tetraxetan). The studies reported herein examine a new pretargeting procedure for delivering therapeutic radionuclides.


METHODS
We prepared a humanized, recombinant tri-Fab bispecific monoclonal antibody (bsmAb) (TF10) using specificity for targeting pancreatic cancer of PAM4 and another Fab binding to a hapten (histamine-succinyl-glycine [HSG]) and tested this in a pretargeting setting with a (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-di-HSG-peptide (pretargeted radioimmunotherapy [PT-RAIT]). Nude mice bearing established Capan-1 human pancreatic cancer xenografts were given TF10 and then received the (90)Y peptide as a single bolus dose 19 h later, or the therapy cycle was fractionated weekly. Other studies examined different combinations with gemcitabine.


RESULTS
PT-RAIT of 18.5 MBq ( approximately 50% of its maximum tolerated dose [MTD]) was as effective as the MTD of (90)Y-PAM4 IgG (5.55 MBq). Three monthly doses of 9.25 MBq of PT-RAIT combined with a monthly cycle of gemcitabine (3 weekly, 6-mg doses) significantly enhanced survival, compared with PT-RAIT alone. Adding gemcitabine as a radiosensitizer to 9.25 MBq of PT-RAIT enhanced objective responses. Weekly fractionation of the PT-RAIT, as compared with a single treatment, improved responses.


CONCLUSIONS
PAM4-based PT-RAIT with (90)Y hapten peptide is an effective treatment for pancreatic cancer, with less toxicity than (90)Y-PAM4 IgG, in this model. Combinations with gemcitabine and dose fractionation of the PT-RAIT enhanced therapeutic responses.
Karacay
Habibe
H
Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA.
Sharkey
Robert M
RM
Gold
David V
DV
Ragland
Dan R
DR
McBride
William J
WJ
Rossi
Edmund A
EA
Chang
Chien-Hsing
CH
Goldenberg
David M
DM
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019583:Dose Fractionation, Radiation; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000737:chemistry; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; C515662:DOTA-tyrosyl-lysyl(histaminyl-succinyl-glycyl)-glutamyl-lysyl(histaminyl-succinyl-glycyl)amide; D006573:Heterocyclic Compounds, 1-Ring; D009842:Oligopeptides; D015021:Yttrium Radioisotopes; D003841:Deoxycytidine; D000093542:Gemcitabine