Radioimmunotherapy with alpha-particle emitting 213Bi-C-functionalized trans-cyclohexyl-diethylenetriaminepentaacetic acid-humanized 3S193 is enhanced by combination with paclitaxel chemotherapy.
OBJECTIVE
Previous experience in solid tumor radioimmunotherapy studies has indicated that greatest therapeutic efficacy is achieved in the treatment of small-volume disease. alpha-Particle-emitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the alpha-particle-emitting bismuth-213 (213Bi) radioimmunotherapy using the humanized anti-Lewis Y (Ley) monoclonal antibody humanized 3S193 (hu3S193).


METHODS
The intracellular localization of hu3S193 in Ley-positive MCF-7 breast carcinoma cells was assessed by confocal microscopy. Cytotoxicity of 213Bi-hu3S193 and apoptosis was assessed using [3H]thymidine incorporation assay and ELISA, respectively. Immunoblotting for gamma-H2AX assessed DNA strand breaks. In vivo efficacy of 213Bi-hu3S193 was assessed using a minimal residual disease model in BALB/c nude mice, with radioconjugate [15, 30, and 60 microCi (9.2 microg)] injected 2 days after s.c. implantation of MCF-7 cells. Radioimmunotherapy was also combined with a single injection of 300 microg paclitaxel to explore improved efficacy. Further, mice with established tumors received 30, 60, or 120 microCi (14.5 microg) of 213Bi-hu3S193 to assess the effect of tumor volume on treatment efficacy.


RESULTS
hu3S193 is internalized via an endosomal and lysosomal trafficking pathway. Treatment with 213Bi-hu3S193 results in >90% cytotoxicity in vitro and induces apoptosis and increased gamma-H2AX expression. 213Bi-hu3S193 causes specific and significant retardation of tumor growth even in established tumors, and efficacy was enhanced by paclitaxel to produce defined complete responses.


CONCLUSIONS
These studies show the potency of alpha-particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Ley-positive malignancies.
Kelly
Marcus P
MP
Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia.
Lee
Fook T
FT
Tahtis
Kiki
K
Smyth
Fiona E
FE
Brechbiel
Martin W
MW
Scott
Andrew M
AM
D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D001729:Bismuth; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use; D017879:Isothiocyanates / Q000627:therapeutic use*; D007983:Lewis Blood Group Antigens / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016499:Radioimmunotherapy; D011868:Radioisotopes; D015996:Survival Rate; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D007140:Immunoglobulin Fab Fragments; D017879:Isothiocyanates; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011868:Radioisotopes; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid; D004369:Pentetic Acid; D017239:Paclitaxel; D001729:Bismuth