Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478.
OBJECTIVE
Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model.


METHODS
The humanized anti-Lewis Y antibody hu3S193 and the EGFR tyrosine kinase inhibitor AG1478 were studied. BALB/c nude mice were engrafted with A431 squamous carcinoma cells. Initial biodistribution properties of the 90Y-CHX-A''-DTPA-hu3S193 were evaluated in this model. In therapy experiments, cohorts of four to five xenografted mice were treated with saline as placebo, 0.4 mg AG1478 i.p. (six doses over 2 weeks), single i.v. injections of unlabeled hu3S193, or 90Y-CHX-A''-DTPA-hu3S193 (12.5, 25, 50, or 100 microCi). The combination of 0.4 mg AG1478 i.p. and 25 microCi 90Y-CHX-A''-DTPA-hu3S193 i.v. was subsequently evaluated in the A431 model.


RESULTS
90Y-CHX-A''-DTPA-hu3S193 retained excellent immunoreactivity after radiolabeling. The biodistribution study showed excellent uptake in tumor (90.33 +/- 38.84%ID/g) peaking at 24 to 72 hours after injection and with prolonged retention. 90Y-CHX-A''-DTPA-hu3S193 significantly inhibited A431 xenograft growth at 25, 50, and 100 microCi doses. The combination of 0.4 mg AG1478 with a single dose of 25 microCi 90Y-CHX-A''-DTPA-hu3S193 resulted in a significant enhancement of efficacy compared with either agent alone (P = 0.013).


CONCLUSIONS
The efficacy of radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 is significantly enhanced by EGFR tyrosine kinase inhibitor AG1478. Further investigations of dosing regimens using EGFR tyrosine kinase inhibitors and radioimmunotherapy in the treatment of EGFR expressing tumors are warranted.
Lee
Fook T
FT
Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia.
Mountain
Angela J
AJ
Kelly
Marcus P
MP
Hall
Cathrine
C
Rigopoulos
Angela
A
Johns
Terrance G
TG
Smyth
Fiona E
FE
Brechbiel
Martin W
MW
Nice
Edouard C
EC
Burgess
Antony W
AW
Scott
Andrew M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D004369:Pentetic Acid / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D020032:Tyrphostins / Q000494:pharmacology*; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
C507850:90Y-CHX-A''-DTPA-hu3S193; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011799:Quinazolines; D019275:Radiopharmaceuticals; D020032:Tyrphostins; D015021:Yttrium Radioisotopes; C101044:RTKI cpd; D004369:Pentetic Acid; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases