Advertisement

Drug Targeting pp 115-132 | Cite as

Effect of Dose, Molecular Size, and Binding Affinity on Uptake of Antibodies

Protocol
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 25)

Abstract

The huge molecular radius of immunoglobulins would seem to be a major drawback for the targeting of solid tumors, because of slow extravasation into tumor interstitium and along plasma half-life. The permeability of normal continuous capillary endothelia to intravascular solutes of different molecular sizes has been determined in animals, mainly for macromolecules, and different sources give data consistent with the graph in Fig. 1 (1, 2, 3). The position of whole antibodies (IgG, mol wt 150 kDa and effective molecular radius 5.5 nm) is well to the right of albumen (66 kDa and 3.5 nm), and they are therefore very slowly extravasated in normal tissues. A F(ab’)2 fragment (100 kDa, 5.06 nm) should not extravasate much faster than the intact molecule on this basis and a monomeric Fab’ fragment (50 kDa, 3.48 nm) still has quite a high molecular radius (4), so a much smaller molecule would be necessary to equilibrate very quickly with extracellular fluid (ECF).
Fig. 1.

Relationship between molecular radius and permeability/surface area product for intact capillaries.

Keywords

Tumor Content Uptake Ratio Dissociation Rate Constant Intact Antibody Molecular Radius 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Garlick, D. G. and Renkin, E. M. (1970) Transport of large molecules from plasma to interstitial fluid and lymph in dogs. Am. J. Physiol. 219, 1595–1605.PubMedGoogle Scholar
  2. 2.
    Arfors, K.-E., Rutili, G., and Svensjo, E. (1979) Microvascular transport of macromol-ecules in normal and inflammatory conditions. Acta. Physiol. Scand. Suppl. 463, 93–103.PubMedGoogle Scholar
  3. 3.
    Taylor, A. E. and Granger, D. N. (1984) Exchange of macromolecules across the microcirculation, in Handbook of Physiology, 4th ed. (Eugene, M. and Rekin, C., eds.), Waverly, Baltimore, MD, pp. 467–520.Google Scholar
  4. 4.
    Pilz, I., Kratky, O., Licht, A., and Sela, M. (1975) Shape and volume of fragments Fab’ and F(ab’)2 of anti-poly (D-alanyl) antibodies in the presence and absence of tetra-D-alanine as determined by small-angle x-ray scattering. Biochemistry 14, 1326–1333.CrossRefPubMedGoogle Scholar
  5. 5.
    Covell, D. G., Barbet, J., Holton, O. D., Black, C. D. V., Parker, R. J., and Weinstein J. N. (1986) Pharmacokinetics of monoclonal immunoglobulin G1, F(ab’)2, and Fab’ in mice. Cancer Res. 46, 3969–3978.PubMedGoogle Scholar
  6. 6.
    Sutherland, R. M., Buchegger, F., Schreyer, M., Vacca, A., and Mach, J. P. (1987) Penetration and binding of radiolabeled anti-carcinoembryonic antigen monoclonal antibodies and their antigen binding fragments in human colon multicellu-lar spheroids. Cancer Res. 47, 1627–1633.PubMedGoogle Scholar
  7. 7.
    Rowlinson-Busza, G., Deonarain, M. P., and Epenetos, A. A. (1996) Comparison of intact monoclonal antibody, its F(ab’) 2 and Fab fragments and recombinant single chain Fv in a human tumor xenograft model. Tumor Target. 2, 37–48.Google Scholar
  8. 8.
    Mason, D. W. and Williams, A. F. (1980) The kinetics of antibody binding to membrane antigens in solution and at the cell surface. Biochem. J. 187, 1–20.PubMedGoogle Scholar
  9. 9.
    Heuser, L. S. and Miller, F. N. (1986) Differential macromolecular leakage from the vasculature of tumors. Cancer 57, 461–464.CrossRefPubMedGoogle Scholar
  10. 10.
    Ackerman, N. B. and Hechmer, P. A. (1978) Studies on the capillary permeability of experimental liver metastases. Surg. Gyn. Obstet. 146, 884–888.Google Scholar
  11. 11.
    Underwood, J. C. E. and Carr, I. (1972) The ultrastructure and permeability characteristics of a transplantable rat sarcoma. J. Pathol. 107, 157–166.CrossRefPubMedGoogle Scholar
  12. 12.
    Papadimitriou, J. M. and Woods, A. E. (1975) Structural and functional characteristics of the microcirculation in neoplasms. J. Pathol. 116, 65–72.CrossRefGoogle Scholar
  13. 13.
    Peterson, H.-I., Appelgren, L., Lundborg, G., and Rosengren, B. (1973) Capillary permeability of two transplantable rat tumours as compared with various normal organs of the rat. Bibl. Anat. 12, 511–518.PubMedGoogle Scholar
  14. 14.
    Gerlowski, L. E. and Jain, R. K. (1986) Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305.CrossRefPubMedGoogle Scholar
  15. 15.
    Rostock, R. A., Klein, J. L., Kopher, K. A., and Order, S. E. (1984) Variables affecting the tumor localization of 131I-anti-ferritin in experimental hepatoma. Amer. J. Clin. Oncol. 6, 9–18.CrossRefGoogle Scholar
  16. 16.
    Otsuka, F. L. and Fleishman, J. B. (1986) Comparative studies using 125I-and 111In-labeled monoclonal antibodies. Eur. J. Nucl. Med. 11, 295–299.Google Scholar
  17. 17.
    Badger, C. C., Krohn, K. A., Peterson, A. V., Shulman, H., and Bernstein, I. D. (1985) Experimental radiotherapy of murine lymphoma with 131I-labeled anti-Thy 1. 1 monoclonal antibody. Cancer Res. 45, 1536–1544.PubMedGoogle Scholar
  18. 18.
    Jakowatz, J. G., Beatty, B. G., Vlahos, W. G., Porudominsky, D., Philben, V. J., Williams, L. E., Paxton, R. J., Shively, J. E., and Beatty, J. D. (1985) High specific activity 111In-labeled anticarcinoembryonic antigen monoclonal antibody: biodistribution and imaging in nude mice bearing human colon cancer xenografts. Cancer Res. 45, 5700–5706.PubMedGoogle Scholar
  19. 19.
    Rogers, G. T., Harwood, P. J., Pedley, R. B., Boden, J., and Bagshawe, K. D. (1986) Dose-dependent localisation and potential for therapy of F(ab’)2 fragments against CEA studied in a human tumour xenograft model. Br. J. Cancer 54, 341–344.CrossRefPubMedGoogle Scholar
  20. 20.
    Washburn, L. C., Sun, T. T., Lee, Y. C., Byrd, B. L., Crook, J. E., and Steplewski, Z. (1987) Y-90-labeled monoclonal antitumour antibodies: effect of purification method and coinjection of unlabeled antibody. J. Nucl. Med. 28, 721.Google Scholar
  21. 21.
    Sharkey, R. M., Primus, F. J., and Goldenberg, D. M. (1987) Antibody protein dose and radioimmunodetection of GW-39 human colon tumor xenografts. Int. J. Cancer 39(9), 611–617.CrossRefPubMedGoogle Scholar
  22. 22.
    Kennel, S. J., Falcioni, R., and Wesley, J. W. (1991) Microdistribution of specific rat monoclonal antibodies to mouse tissues and human tumour xenografts. Cancer Res. 51, 1529–1536.PubMedGoogle Scholar
  23. 23.
    Boerman, O. C., Sharkey, R. M., Wong, G. Y., Blumenthal, R. D., Aninipot, R. L., and Goldenberg, D. M. (1992) Influence of antibody protein dose on therapeutic efficacy of radioiodinated antibodies in nude mice bearing GW-39 human tumor. Cancer Immunol. Immunother. 35, 127–134.CrossRefPubMedGoogle Scholar
  24. 24.
    Halpern, S. E., Dillman, R. O., Witztum, M. D., Shega, J. F., Hagan, P. L., Burrows, W. M., Dillman, J. B., Clutter, M. L., Sobol, R. E., Frincke, J. M., Bartholomew, R. M., David, G. S., and Carlo, D. J. (1985) Radioimmunodetection of melanoma utilising In-111 96.5 monoclonal antibody: a preliminary report. Radiology 155, 493–499.PubMedGoogle Scholar
  25. 25.
    Murray, J. L., Rosenblum, M. G., Sobol, R. E., Bartholomew, R. M., Plager, C. E., Haynie, T. P., Jahns, M. F., Glenn, H. J., Lamki, L., Benjamin, R. S., Papadopoulos, N., Boddie, A. W., Frincke, J. M., David, G. S., Carlo, D. J., and Hersh, E. M. (1985) Radioimmunoimaging in malignant melanoma with 111Indium labeled monoclonal antibody 96.5. Cancer Res. 45, 2376–2381.PubMedGoogle Scholar
  26. 26.
    Carrasquillo, J. A., Bunn, P. A., Keenan, A. M., Reynolds, J. C., Schroff, R. W., Foon, K. A., Ming-Hsu, S., Gazdar, A. F., Mulshine, J. L., Oldham, R. K., Parentesis, P., Horowitz, M., Eddy, J., James, P., and Larson, S. M. (1986) Radioimmunodetection of cutaneous T-cell lymphoma with 111In-labeled T101 monoclonal antibody. N. Engl. J. Med. 315, 673–680.CrossRefPubMedGoogle Scholar
  27. 27.
    Eger, R. R., Covell, D. G., Carrasquillo, J. A., Abrams, P. G., Foon, K. A., Reynolds, J. C., Schroff, R. W., Morgan, A. C., Larson, S. M., and Weinstein, J. N. (1987) Kinetic model for the biodistribution of an 111Indium-labeled monoclonal antibody in humans. Cancer Res. 47, 3328–3336.PubMedGoogle Scholar
  28. 28.
    Murray, J. L., Lamki, L. M., Shanken, L. J., Blake, M. E., Plager, C. E., Benjamin, R. S., Schweighardt, S., Unger, M. W., and Rosenblum, M. G. (1988) Immunospecific saturable clearance mechanisms for Indium-111-labeled anti-melanoma monoclonal antibody 96. 5 in humans. Cancer Res. 48, 4417–4422.PubMedGoogle Scholar
  29. 29.
    Rosenblum, M. G., Murray, J. L., Lamki, L., David, G., and Carlo, D. (1987) Comparative clinical pharmacology of [111In]-labeled murine monoclonal anti-bodies. Cancer Chemother. Pharmacol. 20, 41–47.CrossRefPubMedGoogle Scholar
  30. 30.
    Babaian, R. J., Murray, J. L., Lamki, L. M., Haynie, T. P., Hersh, E. M., Rosenblum, M. G., Glenn, H. J., Unger, M. W., Carlo, D. J., and Von Eschenbach, A. C. (1987) Radioimmunological imaging of metastatic prostate cancer with 111indium-labeled monoclonal antibody PAY 276. J. Urol. 137, 439–443.PubMedGoogle Scholar
  31. 31.
    Kirkwood, J. M., Neumann, R. D., Zoghbi, S. S., Ernstoff, M. S., Cornelius, E. A., Shaw, C., Ziyadeh, T., Fine, J. A., and Unger, M. W. (1987) Scintigraphic detection of metastatic melanoma using indium 111/DTPA conjugated anti-gp 240 antibody (ZME-018). J. Clin. Oncol. 5, 1247–1255.PubMedGoogle Scholar
  32. 32.
    Abdel-Nabi, H. H., Schwartz, A. N., Goldfogel, G., Ortman-Nabi, J. A., Matsuoka, D. M., Unger, M. W., and Wechter, D. G. (1988) Colorectal tumours: scintigra-phy with In-111 anti-CEA monoclonal antibody and correlation with surgical, histopathologic, and immunohistochemical findings. Radiology 166, 747–752.PubMedGoogle Scholar
  33. 33.
    Patt, Y. Z., Lamki, L. M., Haynie, T. P., Unger, M. W., Rosenblum, M. G., Shirkhoda, A., and Murray, J. L. (1988) Improved tumour localisation with increasing dose of Indium-111-labeled anti-CEA monoclonal antibody ZCE-025 in metastatic colorectal cancer. J. Clin. Oncol. 6, 1220–1230.PubMedGoogle Scholar
  34. 34.
    Carrasquillo, J. A., Abrams, P. G., Schroff, R. W., Reynolds, J. C., Woodhouse, C. S., Morgan, A. C., Keenan, A. M., Foon, K. A., Perentis, P., Marshall, S., Horowitz, M., Szymendera, J., Englert, J., Oldham, R. K., and Larson, S. M. (1988) Effect of antibody dose on the imaging and biodistribution of Indium-111 9.2.27 anti-melanoma monoclonal antibody. J. Nucleic Med. 29, 39–47.Google Scholar
  35. 35.
    Carrasquillo, J. A., Sugarbaker, P., Colcher, D., Reynolds, J. C., Esteban, J., Bryant, G., Keenan, A. M., Perentis, P., Yakoyama, K., Simpson, D. E., Ferroni, P., Farkas, R., Schlom, J., and Larson, S. M. (1988) Radioscintigraphy of colon cancer with iodine-131-labeled B72. 3 monoclonal antibodies. J. Nucleic Med. 29, 1022–1030.Google Scholar
  36. 36.
    Lamki, L. M., Murray, J. L., Rosenblum, M. G., Patt, Y. Z., Babaian, R., and Unger, M. W. (1988) Effect of unlabeled monoclonal antibody (Moab) on biodistribution of 11 1indium labeled (Moab). Nucleic Med. Commun. 9, 553–564.CrossRefGoogle Scholar
  37. 37.
    Press, O. W., Eary, J. F., Badger, C. C., Martin, P. J., Appelbaum, F. R., Levy, R., Miller, R., Brown, S., Nelp, W. B., Krohn, K. A., Fisher, D., DeSantes, K., Porter, B., Kidd, P., Thomas, E. D., and Bernstein, I. D. (1989) Treatment of refractory non-Hodgkin’ s lymphoma with radiolabeled MB-1 (anti-CD37) antibody. J. Clin. Oncol. 7, 1027–1038.PubMedGoogle Scholar
  38. 38.
    Griffin, T. W., Bokhari, F., Collino, J., Stochl, M., Bernier, M., Gionet, M., Siebecker, D., Wertheimer, M., Giroves, E. S., Greenfield, L., Houston, L. L., Doherty, P. W., and Wilson, J. (1989) A preliminary pharmacokinetic study of 111In-labeled 260F9 anti-(breast cancer) antibody in patients. Cancer Immunol. Immunother. 29, 43–50.CrossRefPubMedGoogle Scholar
  39. 39.
    Serafini, A. N., Goldenberg, D. M., Higinbotham-Ford, E. A., Silberstein, E. B., Van Heertum, R. L., Kotler, J. A., Balasubramanian, N., Garty, I., and Wlodkowski, T. (1989) A multicenter trial of cancer imaging with fragments of CEA monoclonal antibodies. J. Nucl. Med. 82, 748.Google Scholar
  40. 40.
    Scheinberg, D. A., Straus, D. J., Yeh, S. D., Divgi, C., Gavin-Chesa, P., Graham, M., Pentlow, K., Coit, D., Oettgen, H. F., and Old, L. J. (1990) A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkins lymphoma: effects of tumor burden and antigen expression. J. Clin. Oncol. 8, 792–803.PubMedGoogle Scholar
  41. 41.
    Steward, M. W. and Steensgaard, J. (1983) Antibody Affinity: Thermodynamic Aspects and Biological Significance. CRC, Boca Raton, FL.Google Scholar
  42. 42.
    Kennel, S. J., Foote, L. J., Lanford, P. K., Johnson, M., Mitchell, T., and Braslawsky, G. R. (1983) Direct binding of radio-iodinated monoclonal antibody to tumour cells: significance of antibody purity and affinity for drug targeting or tumour imaging. Hybridoma 2, 297–310.CrossRefPubMedGoogle Scholar
  43. 43.
    Devey, M. E. and Steward, M. W. (1988) The role of antibody affinity in the performance of solid phase assays, in Elisa and Other Solid Phase Immunoassays (Kemeny, D. M. and Chollacombe, S. J., eds.), Wiley, UK, pp. 135–153.Google Scholar
  44. 44.
    Weinstein, J. N., Covell, D. G., Barbet, J., Eger, R. R., Holton, O. D., Talley, M. J., Parker, R. J., and Black, C. D. V. (1987) Local and cellular factors in the phar-macology of monoclonal antibodies, in Membrane Mediated Cytotoxicity (Bonavida, B. and Collier, R. J., eds.), Liss, New York, pp. 279–289.Google Scholar
  45. 45.
    Sharkey, R. M., Primus, F. J., Shochat, D., and Goldenberg, D. M. (1988) Comparison of tumour targeting of mouse monoclonal and goat polyclonal antibodies to carcinoembryonic antigen in the GW-39 human tumour-hamster host model. Cancer Res. 48, 1823–1828.PubMedGoogle Scholar
  46. 46.
    Wang, A.-C., Banjo, C., Fuks, A., Shuster, J., and Gold, P. (1976) Heterogeneity of the protein moiety of carcinoembryonic antigens. Immunol. Commun. 5, 205–210.PubMedGoogle Scholar
  47. 47.
    Olson, W. C., Spitznagel, T. M., and Yarmush, M. L. (1989) Dissociation kinetics of antigen-antibody interactions: studies on a panel of anti-albumin monoclonal antibodies. Mol. Immunol. 26, 129–136.CrossRefPubMedGoogle Scholar
  48. 48.
    Watt, R. M., Herron, J. M., and Voss, E. W. (1980) First order dissociation rates between a subpopulation of high-affinity rabbit anti-fluorescyl IgG antibody and homologous ligand. Mol. Immunol. 17, 1237–1243.CrossRefPubMedGoogle Scholar
  49. 49.
    Morrison, J. F. and Walsh, C. T. (1988) The behaviour and significance of slow-binding enzyme inhibitors. Adv. Enzymol. 61, 201–301.PubMedGoogle Scholar
  50. 50.
    Aisen, P. and Leibman, A. (1978) Thermodynamic and accessibility factors in the specific binding of iron to human transferrin, in Transport by Proteins (Blauer, G. and Sund, H., eds.), Walter de Gruyter, Berlin, pp. 277–294.Google Scholar
  51. 51.
    Green, N. M. (1963) Avidin. The nature of the biotin-binding site. Biochem. J. 89, 599–609.PubMedGoogle Scholar
  52. 52.
    Absolom, D. R. and van Oss, C. J. (1986) The nature of the antigen-antibody bond and the factors affecting its association and dissociation. CRC Crit. Rev. Immunol. 6, 1–46.PubMedGoogle Scholar
  53. 53.
    Thomas, G. D., Chappell, M. J., Dykes, P. W., Ramsden, D. B., Godfrey, K. R., Ellis, J. R. M., and Bradwell, A. R. (1989) Effect of dose, molecular size, affinity, and protein binding on tumour uptake of antibody or ligand: a biomathematical model. Cancer Res. 49, 3290–3296.PubMedGoogle Scholar
  54. 54.
    Chappell, M. J., Thomas, G. D., Godfrey, K. R., and Bradwell, A. R. (1991) Optimal tumour targeting by antibodies: development of a mathematical model. J. Pharmacokin Biopharm. 19, 227–260.CrossRefGoogle Scholar
  55. 55.
    Jacquez, J. A. (1985) Compartmental Analysis in Biology and Medicine, University of Michigan Press, Ann Arbor, MI.Google Scholar
  56. 56.
    Shampine, L. F. and Gear, C. W. (1979) A user’s view of solving stiff differential equations. SIAM Rev. 21, 1–17.CrossRefGoogle Scholar
  57. 57.
    Fatunla, S. O. (1988) Numerical Methods for Initial Value Problems in Ordinary Differential Equations. Academic, New York.Google Scholar
  58. 58.
    Chappell, M. J. and Godfrey, K. R. (1990) Structural identifiability of a model developed for optimal tumour targeting by antibodies using the similarity transformation approach. University of Warwick Control and Instrument Systems Centre, Report No. 7.Google Scholar
  59. 59.
    Curtis, A. R. and Sweetenham, W. P. (1987) FACSIMILE/CHEKMAT User’s Manual. Harwell Laboratory Report, UK Atomic Energy Authority, Atomic Energy Research Establishment, Computer Science and Systems Division, 12805.Google Scholar
  60. 60.
    Attard, A. R., Chappell, M. J., Bennett, J., Thomas, G. D., Godfrey, K. R., Dykes, P. W., and Bradwell, A. R. (1991) Optimal tumor targeting by antibodies: Validation of a mathematical model. Antibody Immunoconj. Radiopharmaceu. 4, 435–441.Google Scholar
  61. 61.
    Thomas, G. D. (1995) Development of a model of tumour targeting to predict optimal conditions for therapy. MD Thesis, University of London, London.Google Scholar
  62. 62.
    Bhat, T. N., Bentley, G. A., Fischmann, T. O., Boulot, G., and Poljak, R. J. (1990) Small rearrangements in structures of Fv and Fab fragments of antibody D1. 3 on antigen binding. Nature 347, 483–485.CrossRefPubMedGoogle Scholar
  63. 63.
    Cheong, H. S., Chang, J. S., Park, J. M., and Byun, S. M. (1990) Affinity enhancement of bispecific antibody against two different epitopes in the same antigen. Biochem. Biophys. Res. Commun. 173, 795–800.CrossRefPubMedGoogle Scholar
  64. 64.
    Ehrlich, P. H., Moyle, W. R., Moustafa, Z. A., and Canfield, R. E. (1982) Mixing two monoclonal antibodies yields enhanced affinity for antigen. J. Immunol. 128, 2709–2713.PubMedGoogle Scholar
  65. 65.
    Holmes, N. J. and Parham, P. (1983) Enhancement of monoclonal antibodies against HLA-A2 is due to antibody bivalency. J. Biol. Chem. 258, 1580–1586.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2000

Authors and Affiliations

  1. 1.Department of Clinical OncologyDerbyshire Royal InfirmaryDerbyUK

Personalised recommendations