Enhanced efficacy of 90Y-radiolabeled anti-Lewis Y humanized monoclonal antibody hu3S193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model.
Radioimmunotherapy (RIT) of solid tumor is often limited in efficacy because of restrictions in achieved tumor dose. In an effort to overcome this, the combination of RIT with other therapeutic modalities was investigated in an animal model of breast carcinoma. The rationale for this combined-modality RIT (CMRIT) was to increase the therapeutic efficacy of RIT through the use of paclitaxel to arrest cells in the radiosensitive G(2)/M phase of the cell cycle.


METHODS
In this study, the biodistribution and therapeutic efficacy of (90)Y-radiolabeled humanized anti-Lewis Y hu3S193 monoclonal antibody ((90)Y-hu3S193) RIT in combination with paclitaxel chemotherapy was explored in a Lewis Y-expressing MCF-7 tumor xenografted BALB/c nude mouse model of breast cancer.


RESULTS
Biodistribution studies demonstrated excellent tumor targeting and limited normal tissue uptake by (90)Y-hu3S193. A therapeutic study with established tumors assessed (90)Y-hu3S193 as a single agent and demonstrated significant antitumor effects in all animals receiving a single intravenous 1.85 or 3.70 MBq dose of this treatment compared with phosphate-buffered saline placebo controls (P = 0.0008 vs. P < 0.0001). Complete responses were observed in all animals in the 3.70 MBq study arm for the duration of the study. Single-dose (90)Y-hu3S193 plus paclitaxel (600 microg) CMRIT displayed improved efficacy over single-modality therapies, with a significant difference (P < 0.0001) between the mean percentage change in tumor volume in mice receiving 0.46 MBq (90)Y-hu3S193 alone and when combined with 600 mug paclitaxel.


CONCLUSIONS
The significant efficacy of (90)Y-hu3S193 and paclitaxel CMRIT at low radiation doses in this model of breast carcinoma indicates its therapeutic potential and warrants further investigation into this promising therapeutic approach.
Kelly
Marcus P
MP
Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria 3084, Australia.
Lee
Fook T
FT
Smyth
Fiona E
FE
Brechbiel
Martin W
MW
Scott
Andrew M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007983:Lewis Blood Group Antigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D017239:Paclitaxel / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D017239:Paclitaxel