Improved antibody targeting with interferon-alpha-2b conjugate.
This investigation is based on a hypothesis that a biological response modifier, interferon-alpha-2b (IFN), when conjugated with a specific monoclonal antibody (mAb) and given to tumor-bearing animals before the administration of radiolabeled mAb, may not only augment the tumor uptake but may also impede the liver and blood uptake, because the mAb associated with the conjugate may block nonspecific hepatic binding sites and scavenge circulating antigens. ME 31.3 and anti-carcinoembryonic antigen (CEA) F-6 (IgG-2a) specific for human melanoma and colorectal carcinoma, respectively, were chosen as prototype mAbs and conjugated with IFN-alpha-2b for evaluation in athymic nude mice bearing respective experimental tumors. The mAb specificity for the tumor cell line was examined by binding assays and Kd values were determined to be 1.96 x 10(-9) M and 5.9 x 10(-9) M for ME 31.3 and anti-CEA F-6, respectively. Thirty micrograms of conjugate, prepared chemically and purified chromatographically (IFN-mAb:1:1), was administered intravenously to each animal and 3 h later followed by an intravenous injection of 20 micrograms F(ab')2 of corresponding mAb labeled with 300 muCi Tc-99m (1.5 Ci/mmol). Twenty-four hours later, in melanoma-bearing animals, not only did the tumor uptake increase, but also the liver uptake decreased by 75%. Tumor/muscle and tumor/blood ratios also enhanced by 200 and 500%, respectively. Consistent with ME 31.3, the tumor uptake with anti-CEA F-6 also increased (p = 0.00) and the liver uptake decreased (p = 0.01). Similarly, tumor/muscle (p = 0.01) and tumor/blood (p = 0.02) ratios also increased significantly. Results indicate that IFN:mAb conjugate may improve diagnostic and therapeutic potential of mAbs, and is worthy of further studies.
Thakur
M L
ML
Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107, USA.
Li
J
J
Donegan
M
M
Pallela
V R
VR
Kolan
H
H
Duggaraju
R
R
Maish
D
D
Srivastava
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000532:radiotherapy; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000532:radiotherapy*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000276:immunology; D016499:Radioimmunotherapy; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D011994:Recombinant Proteins