| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. S., D. E., D. C., A. M., K. S.]; Battelle Memorial Institute, Columbus, Ohio 43201 [D. H., L. S. M.]; and Division of Nuclear Medicine, The Ohio State University, Columbus, Ohio 43210 [G. H.]
The effect of the relative affinity (Ka) on the antitumor efficacy of monoclonal antibodies (MAbs) has been questioned. It has previously been shown in experimental models that the use of MAbs with higher relative Kas manifests itself in a higher percentage of injected dose of MAb bound to tumor. On the other hand, mathematical models have proposed that the use of higher affinity MAbs may be disadvantageous for antitumor effects, since higher Ka MAbs would bind more antigen and prevent penetration of MAb through tumor. To test this hypothesis, three MAbs reacting to the human pancarcinoma antigen TAG-72 were used as radioimmunoconjugates for therapeutic efficacy versus the LS-174T human colon carcinoma xenograft. MAbs B72.3, CC49, and CC83 have all been shown by depletion studies to react to the same molecule and to all react with overlapping epitopes. While the relative Ka of B72.3 is 2.5 x 109 M–1, the relative Kas of CC49 and CC83 are 16.2 and 27.7 x 109 M–1, respectively. Each MAb was radiolabeled with 131I, and each radioimmunoconjugate was assayed at five dose levels for therapeutic efficacy using the human xenograft model. The results of these studies demonstrate substantial therapeutic advantage of the higher affinity MAbs CC49 and CC83 versus B72.3 at every dose level. While 500 µCi of B72.3 were required to reduce tumor growth in only a minority of tumor-bearing animals, the use of the same amount or less of the radioimmunoconjugates of CC49 or CC83 resulted in strong antitumor effects in 80 to 100% of tumor-bearing animals. Thus, stronger antitumor effects were seen using as little as 2.5- to 3-fold less of the higher Ka immunoconjugates CC49 and CC83 as compared with B72.3. While we acknowledge the potential disadvantages of higher Ka MAbs in some situations, at least the experimental studies and model system described here show that a distinct therapeutic advantage exists with the use of higher affinity immunoconjugates.
1 To whom requests for reprints should be addressed, at the Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Building 10, Room 8B07, Bethesda, MD 20892.
2 Present address: University of Nebraska Medical Center, Department of Pathology and Microbiology, Omaha, NE 68198.
3 Present address: Academia Nacional de Medicina, Centro de Estudios Oncologilos, Buenos Aires, Argentina.
4 Present address: Neoprobe Corporation, Columbus, OH 43212.
Received 8/ 7/91. Accepted 12/13/91.
This article has been cited by other articles:
|
|
 |
|
  D. J. Buchsbaum, M.B. Khazaeli, D. B. Axworthy, J. Schultz, T. R. Chaudhuri, K. R. Zinn, M. Carpenter, and A. F. LoBuglio Intraperitoneal Pretarget Radioimmunotherapy with CC49 Fusion Protein Clin. Cancer Res., November 15, 2005; 11(22): 8180 - 8185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Baranowska-Kortylewicz, M. Abe, K. Pietras, Z. P. Kortylewicz, T. Kurizaki, J. Nearman, J. Paulsson, R. L. Mosley, C. A. Enke, and A. Ostman Effect of Platelet-Derived Growth Factor Receptor-{beta} Inhibition with STI571 on Radioimmunotherapy Cancer Res., September 1, 2005; 65(17): 7824 - 7831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. De Pascalis, N. R. Gonzales, E. A. Padlan, P. Schuck, S. K. Batra, J. Schlom, and S. V. S. Kashmiri In Vitro Affinity Maturation of a Specificity-Determining Region-Grafted Humanized Anticarcinoma Antibody: Isolation and Characterization of Minimally Immunogenic High-Affinity Variants Clin. Cancer Res., November 15, 2003; 9(15): 5521 - 5531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lu, J. Shen, M. D. Vil, H. Zhang, X. Jimenez, P. Bohlen, L. Witte, and Z. Zhu Tailoring in Vitro Selection for a Picomolar Affinity Human Antibody Directed against Vascular Endothelial Growth Factor Receptor 2 for Enhanced Neutralizing Activity J. Biol. Chem., October 31, 2003; 278(44): 43496 - 43507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Goel, S. Augustine, J. Baranowska-Kortylewicz, D. Colcher, B. J. M. Booth, G. Pavlinkova, M. Tempero, and S. K. Batra Single-Dose versus Fractionated Radioimmunotherapy of Human Colon Carcinoma Xenografts Using 131I-labeled Multivalent CC49 Single-chain Fvs Clin. Cancer Res., January 1, 2001; 7(1): 175 - 184. [Abstract] [Full Text]
|
|
|
|
|
|
A. Goel, D. Colcher, J. Baranowska-Kortylewicz, S. Augustine, B. J. M. Booth, G. Pavlinkova, and S. K. Batra Genetically Engineered Tetravalent Single-Chain Fv of the Pancarcinoma Monoclonal Antibody CC49: Improved Biodistribution and Potential for Therapeutic Application Cancer Res., December 1, 2000; 60(24): 6964 - 6971. [Abstract] [Full Text]
|
|
|
|
|
|
L. S. Zuckier, E. Z. Berkowitz, R. J. Sattenberg, Q. H. Zhao, H. F. Deng, and M. D. Scharff Influence of Affinity and Antigen Density on Antibody Localization in a Modifiable Tumor Targeting Model Cancer Res., December 1, 2000; 60(24): 7008 - 7013. [Abstract] [Full Text]
|
|
|
|
|
|
J. W. G. Stroomer, J. C. Roos, M. Sproll, J. J. Quak, K.-H. Heider, B. J. Wilhelm, J. A. Castelijns, R. Meyer, M. O. Kwakkelstein, G. B. Snow, et al. Safety and Biodistribution of 99mTechnetium-labeled Anti-CD44v6 Monoclonal Antibody BIWA 1 in Head and Neck Cancer Patients Clin. Cancer Res., August 1, 2000; 6(8): 3046 - 3055. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Tamura, D. E. Milenic, M. Iwahashi, E. Padlan, J. Schlom, and S. V. S. Kashmiri Structural Correlates of an Anticarcinoma Antibody: Identification of Specificity-Determining Residues (SDRs) and Development of a Minimally Immunogenic Antibody Variant by Retention of SDRs Only J. Immunol., February 1, 2000; 164(3): 1432 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, M. Hanibuchi, S. Yano, Y. Tanaka, I. Fujino, M. Inoue, T. Takezawa, K. Shitara, S. Sone, and N. Hanai Apoptosis Induction of Human Lung Cancer Cell Line in Multicellular Heterospheroids with Humanized Antiganglioside GM2 Monoclonal Antibody Cancer Res., October 1, 1999; 59(20): 5323 - 5330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pavlinkova, B. J. M. Booth, S. K. Batra, and D. Colcher Radioimmunotherapy of Human Colon Cancer Xenografts Using a Dimeric Single-Chain Fv Antibody Construct Clin. Cancer Res., September 1, 1999; 5(9): 2613 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. COLCHER, G. PAVLINKOVA, G. BERESFORD, B. J.M. BOOTH, and S. K. BATRA Single-Chain Antibodies in Pancreatic Cancer Ann. N.Y. Acad. Sci., June 30, 1999; 880(1): 263 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Berk, F. Yuan, M. Leunig, and R. K. Jain Direct in vivo measurement of targeted binding in a human tumor xenograft PNAS, March 4, 1997; 94(5): 1785 - 1790. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
