Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35.
The purpose of this study was to investigate the therapeutic efficacy of-and to estimate the absorbed dose to-tumor cells from radioimmunotherapy (RIT) in an ovarian cancer model using the alpha-particle-emitting nuclide (211)At labeled to monoclonal antibody (mAb) MX35. Previous studies on mAb MOv18 did not allow for dosimetry because of antigen shedding in vitro.


METHODS
Five-week-old female nude BALB/c nu/nu mice were inoculated intraperitoneally with 1 x 10(7) cells of the human tumor cell line OVCAR-3. Three weeks later, the animals were given approximately 400, 800, or 1,200 kBq of (211)At-labeled mAb MX35 intraperitoneally. As controls, one group of animals was injected with unlabeled mAb and another group was injected with phosphate-buffered saline (PBS). Another group was given approximately 400 kBq of (211)At labeled to the previously investigated mAb MOv18 for efficacy comparison. Two months after treatment, the animals were sacrificed and the presence of macroscopic and microscopic tumors, as well as ascites, was determined. The absorbed dose to tumor cells on the peritoneal surface was estimated in terms of the sum of a specific and a nonspecific contribution. The specific contribution, arising from mAbs binding to the antigenic sites on the cell membrane, was calculated using a dynamic compartment model developed in-house and Monte Carlo software. The model used as input values the number of mAbs injected into the abdominal cavity, N(mAb), the specific activity, A(sp), the association rate constant, k(on), and the maximal number of mAbs bound per cell, B(max)-all determined by in vitro experiments. This specific component of the absorbed dose was calculated for assumed cell cluster sizes with radii of 25, 50, and 100 microm. The nonspecific contribution to the absorbed dose was derived from unbound mAbs freely circulating in the abdominal cavity, also using the Monte Carlo software.


RESULTS
In the control groups given unlabeled MX35 or PBS, all 18 animals had ascites, 6 of 9 animals in each group had macroscopic tumors, and all animals had microscopic growth. In the 3 groups given different amounts of (211)At-MX35, only 3 of 25 animals developed ascites. None of these animals had any sign of macroscopic tumors, but 8 had microscopic growth. In the group given (211)At-MOv18, no animals had ascites or macroscopic tumors, but 3 of 10 animals had microscopic tumors. After injecting 400 kBq of (211)At-MX35, the absorbed dose due to specific binding, for a cell cluster with a radius of 50 microm, ranged from 413 to 223 Gy between 0- and 45-microm distance from the cluster center, assuming a homogeneous distribution of (211)At-MX35 in the cluster. The contribution from unbound (211)At-MX35 and (211)At-MX35 only distributed on the cluster surface, for this cluster size, ranged from 7 to 14 Gy and from 29 to 94 Gy, between 0- and 45-microm distance from the cluster center, respectively. The calculated total absorbed doses are in a clinically relevant range and were effective as verified in the nude mice with subclinical intraperitoneal growth of OVCAR-3 cells.


CONCLUSIONS
(211)At-MX35 injected intraperitoneally exhibits a high efficacy when treating micrometastatic growth of the ovarian cancer cell line OVCAR-3 on the peritoneum of nude mice.
Elgqvist
Jörgen
J
Department of Radiation Physics, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden. jorgen.elgqvist@radfys.gu.se
Andersson
Håkan
H
Bäck
Tom
T
Hultborn
Ragnar
R
Jensen
Holger
H
Karlsson
Börje
B
Lindegren
Sture
S
Palm
Stig
S
Warnhammar
Elisabet
E
Jacobsson
Lars
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001822:Body Burden; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D011874:Radiometry / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
C507514:211At-labeled monoclonal antibody MX35; D000911:Antibodies, Monoclonal; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals