Clinical evaluation of tumor targeting with the anticarcinoembryonic antigen murine monoclonal antibody fragment, MN-14 F(ab)2.
BACKGROUND
The initial clinical experience with the second-generation, high-affinity, MN-14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA) monoclonal antibody (MoAb) in patients with CEA-producing tumors was reported previously. A bivalent fragment of this MoAb, MN-14 F(ab)2, was prepared, and its pharmacokinetics, targeting properties, dosimetry, and immunogenicity were investigated.


METHODS
MN-14 F(ab)2(0.6-29 mg) was labeled with 131I(7.7-269 millicuries and injected into 28 patients with CEA-producing cancers. External scintigraphy was used to evaluate tumor targeting. Quantitative external scintigraphy methods were used to determine the organ and tumor radiation doses.


RESULTS
The overall sensitivity of tumor targeting on a lesion basis was 86%, similar to that reported previously for MN-14 whole IgG. The biologic T1/2's for the fragment in the blood and total body (in hours) were 16.8 +/- 4.1 and 59.4 +/- 9.4, respectively, compared with 27.3 +/- 15.7 and 69.6 +/- 32.2 reported for MN-14 IgG. Depending on the protein dose given, high plasma CEA levels (>100ng/ML) resulted in a significant alteration of MoAb pharmacokinetics and organ dosimetry. Individual tumors received an average dose of 10.7 +/- 7.3 centigray [cGy]/mCi, and the tumor-to-total body, red marrow, lung, liver, and kidney dose ratios were 16.8 +/- 11.1, 5.6 +/- 3.6, 5.1 +/- 3.9, 6.0 +/- 3.8, and 3.1 +/- 2.0, respectively (mean + standard deviation [SD]). Only 9 of 18 patients (50%) injected with >4 mg (range: 4-52.1 mg) of MN-14 F(ab)2 developed significant levels of human antimouse antibodies, suggesting that the F(ab)2 may be less immunogenic than the intact IgG.


CONCLUSIONS
MN-14 F(ab)2 exhibits a similar targeting sensitivity and tumor dose as reported previously for the IgG form. The lower red marrow doses combined with lower immunogenicity expected for this agent, may make it a suitable alternative for future imaging and therapeutic applications.
Juweid
M
M
Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Newark, New Jersey 07103, USA.
Sharkey
R M
RM
Behr
T M
TM
Swayne
L C
LC
Dunn
R
R
Ying
Z
Z
Siegel
J A
JA
Hansen
H J
HJ
Goldenberg
D M
DM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D000936:Antigen-Antibody Complex / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood / Q000276:immunology*; D005260:Female; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D000922:Immunotoxins / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000000981:diagnostic imaging / Q000628:therapy; D011877:Radionuclide Imaging
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins