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Pharmacokinetics of an HIV-1 gp120-specific chimeric antibody in patients with HIV-1 disease

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Biotherapy

Abstract

The pharmacokinetics of mouse V/human C (γ1,κ) chimeric monoclonal antibody CGP47 439 specific for the principal neutralizing determinant of human immunodeficiency virus type 1 (HIV-1) was studied in patients with stage IV HIV-1 disease in an open-labeled phase I/IIA trial. Twelve male patients were enrolled and nine completed the study. Patients were divided into three groups according to the extent of CGP 47 439 to bind to gp120 from their viral isolates: undetectable for group 1, modestly reactive for group 2, and strongly reactive for group 3. A first dose of 1, 10, or 25 mg was administered by intravenous infusion to group 1, group 2 and group 3 patients, respectively. The patients then received seven doses of 50, 100, or 200 mg, respectively, every three weeks. CGP 47 439 serum concentrations were determined by an ELISA using monoclonal antibody AB19-4 specific for the idiotope of CGP 47 439. Half an hour after infusion only 25.5–36.1% of the administered antibody was found in the serum, reflecting its rapid distribution in the extravascular space and possibly binding to gp120 antigen in some of the patients. The terminal elimination half-life (T1/2) was 16.2 days in group 1 patients, 9.7 days in group 2 and in group 3 patients 7.5 days and 9.1 days. An antibody response to CGP 47 439 was not a factor in determining elimination rates, because only very low and transient responses were found in three patients. These results suggest that the reactivity of CGP 47 439 with HIV-1 gp120 contributed to its elimination in HIV-1 infected patients.

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Abbreviations

AIDS:

aquired immune deficiency syndrome

ARC:

AIDS-related complex

HIV-1:

human immune deficiency virus type 1

gp120:

envelope glycoprotein with 120 KD molecular weight

V3:

variable domain of gp120

PND:

principle neutralizing determinant of gp120

IgG:

immunoglobulin G

CD4+ lymphocytes: lymphocytes expressing the CD4 marker:

VH and VL variable heavy and variable light chain region of an antibody

Cγ1 and CK :

constant heavy chain region of gamma l and constant K light chain region of an antibody

anti-id:

anti-idiotypic

AUC:

area under curve

T1/2 :

terminal elimination half-life

ELISA:

enzyme-linked imuno sorbent assay

PBS:

phosphate buffered saline

NP-40:

detergent

CDC:

center of disease control

GMP:

good manufacturing practice

References

  1. Clark SJ, Saag MS, Decker WD, Campell-Hill S, Roberson JL, Veldkamp PT, Kappes JC, Hahn BH, Shaw GM. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. New Engl J Med 1991; 324: 954–60.

    PubMed  Google Scholar 

  2. Daar ES, Moudgil T, Meyer RD, Ho DD. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. New Engl J Med 1991; 324: 361–4.

    Google Scholar 

  3. Paul DA, Falle LA, Kessler HA, Chase RM, Blaauw B, Chudwin BS, Landay AL. Correlation of serum HIV antigen and antibody with clinical status in HIV-infected patients. J Med Virol 1987; 22: 357–63.

    PubMed  Google Scholar 

  4. Robert-Guroff M, Goedert JJ, Naungel CJ, Jennings AM, Blattner WA, Gall RC. Spectrum of HIV-1 neutralizing antibodies in a cohort of homosexual men: results of a 6-year prospective study. AIDS Res Human Retroviruses 1988; 4: 343–9.

    Google Scholar 

  5. Jackson GG, Perkins JT, Rubenis M, Paul DA, Knigge M, Despotes JC, Spencer P. Passive immunoneutralization of human immunodeficiency virus in patients with advanced AIDS. The Lancet 1988; ii: 647–52.

    Google Scholar 

  6. Karpas A, Hill F, Youle M, Cullen V, Gray J, Byron N, Hayhoe F, Tenant-Flowers M, Howard M, Gilgen D, Oates JK, Hawkins D, Gazzard B. Effects of passive immunization in patients with acquired immunodeficiency syndrome-related complex and acquired immunodeficiency syndrome. Proc Natl Acad Sci USA 1988; 85: 9234–7.

    PubMed  Google Scholar 

  7. Karpas A, Hewlitt IK, Hill F, Gray J, Byron N, Gilgen D, Bally V, Oates JK, Gazzard B, Epstein JE. Polymerase chain reaction evidence for human immunodeficiency virus 1 neutralization by passive immunization in patients with AIDS and AIDS-related complex. Proc Natl Acad Sci USA 1990; 87: 7613–7.

    PubMed  Google Scholar 

  8. Vittecoq D, Mattlinger B, Barré-Sinoussi F, Courouce AM, Rouzioux C, Doinel C, Bary M, Viard JP, Bach JF, Rouger P, Lefrere JJ. Passive immunotherapy in AIDS: a randomized trial of serial human immunodeficiency virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. J Inf Dis 1992; 165: 364–8.

    Google Scholar 

  9. Putkonen P, Thorstensson R, Ghavamzadeh L, Albert J, Hild K, Biberfeld G, Norrby E. Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys. Nature 1991; 352: 436–8.

    PubMed  Google Scholar 

  10. Emini EA, Schleif WA, Nunberg JH, Conley AJ, Eda Y, Tokiyoshi S, Putney SD, Matsushita S, Cobb KE, Jett CM, Eichberg JW, Murthy KK. Prevention of HIV-1 infection in chimpanzees by gp120 V3 domain-specific monoclonal antibody. Nature 1992; 344: 728–30.

    Google Scholar 

  11. Fung MSC, Sun C, Sun NC, Chang NT, Chang TW. Monoclonal antibodies that neutralize HIV-1 virions and inhibit syncyntium formation by infected cells. BioTechnology 1987; 5: 940–6.

    Google Scholar 

  12. Liou RS, Rosen EM, Fung MSC, Sun NC, Sun C, Gordon W, Chang NT, Chang TW. A chimeric mouse-human antibody that retains specificity for HIV gp120 and mediates the lysis of HIV-infected cells. J Immunol 1989; 143: 3967–75.

    PubMed  Google Scholar 

  13. Safrit JT, Fung MSC, Andrews CA, Braun DG, Sun WNC, Chang TW, Koup RA. Hu-PBL-SCID mice can be protected from HIV-1 infection by passive transfer of monoclonal antibody to the principal neutralizing determinant of the envelope gp120. AIDS 1992; 7: 15–21.

    Google Scholar 

  14. Braun DG, McKinney S, Gordon W, Zühlke U, Gudat F, Liou RS, Spähni U, Bee W, Pfannkuch F, Fung MSC, Chang NT. A mouse/human chimeric monoclonal antibody to HIV-1 qualifying for a phase I trial in patients with AIDs. In: Abraham NG, Marks P, Konwalinka G, Sachs L, Tawassoli M, eds. Molecular Biology of Haematopoiesis 1992; 2: 437–48. Intercept Ltd, Andover, Hants, UK.

    Google Scholar 

  15. Liou RS, Fung MSC, Zühlke U, Gudat F, McKinney S, Gordon W, Bee W, Botta L, Gygax D, Chang TW, Chang NT, Braun DG. Mouse/human chimeric anti-HIV-1 gp120 antibody to the principal neutralizing determinant: tolerability and pharmacokinetics in cynomolgus monkeys, Maccacca fascicularis. Biotherapy 1992; 5: 291–9.

    PubMed  Google Scholar 

  16. Fung MSC, Sun CRY, Liou RS, Gordon W, Chang NT, Chang TW, Sun NC. Monoclonal anti-idiotypic antibody mimicking the principal neutralization site of HIV-1 gp120 induces HIV-1 neutralizing antibodies in rabbits. J Immunol 1990; 145: 2199–206.

    PubMed  Google Scholar 

  17. Holmes K, Fowlkes BJ. Immunofluorescence and cell sorting. In: Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W, eds. Current Protocols in Immunology. New York: Greene Publishing and Wiley-Interscience, 1991: 5.4.3.

    Google Scholar 

  18. Byrkit DR. Linear regression analysis. In:Statistics today. A comprehensive introduction. Menlo Park, CA: The Benjamin/Cummings Publishing Co. Inc., 1987: 712.

    Google Scholar 

  19. Wagner JG. In: Fundamentals of clinical pharmacokinetics. Hamilton, IL: Drug Intelligence Publications, Inc. 1979; 71.

    Google Scholar 

  20. Gibaldi M, Perrier D. Appendix E, Prediction of drug concentrations on multiple dosing using the principle of superposition. In: Swarbrick J, ed. Pharmacokinetics 2nd Edition. New York-Basle: Marcel Dekker Inc., 1982: 451–7.

    Google Scholar 

  21. Scheinberg DA Houghton AN. Current status of antitumor therapy with monoclonal antibodies. Oncology 1987; 1: 33–40.

    PubMed  Google Scholar 

  22. Schlom J. Monoclonal antibodies in cancer therapy. BioPharm 1988; 1: 33–40.

    Google Scholar 

  23. Schroff RW, Foon KA, Beatty SM, Oldham RK, Morgan AC. Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 1985; 45: 879–85.

    PubMed  Google Scholar 

  24. Khazaeli MB, Saleh M, Wheeler RH, Huster W, Holden H, Carrano R, Lo Buglio AF. Phase I trials of multiple large doses of murine monoclonal antibody CO17-1A. II. Pharmacokinetics and immune response. J Natl Cancer Inst 1988; 80: 937–42.

    PubMed  Google Scholar 

  25. Wahren B, Bratt G, Hinkula J, Gilljam G, Nordlund S, Broliden PA, Akerblom L, Morein B, Sandström E. Monoclonal antibodies given as passive treatment to HIV-infected individuals. In: Retroviruses of human AIDS and related animal diseases. Girard M, Valette L, eds. 5e collogue des «Cent Gardes», Pasteur Mérieux 1990: 263–7.

  26. Morrison SL. Transfectoma provide novel chimeric antibodies. Science 1985; 229: 1202–7.

    PubMed  Google Scholar 

  27. Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 1988; 332: 323–7.

    PubMed  Google Scholar 

  28. Lo Buglio AF, Wheeler RH, Trang J, Haynes A, Rogers K, Harvey EB, Sun L, Ghrayeb J, Khazaeli MB. Mouse/ human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci USA 1989; 86: 4220–4.

    PubMed  Google Scholar 

  29. Khazaeli MB, Saleh MN, Liu TP, Meredith RF, Wheeler RH, Baker TS, King D, Secher D, Allen L, Rogers K, Colcher D, Schlom J, Shochat D, Lo Buglio AF. Pharmacokinetics and immune response of131I-chimeric mouse/human B72.3 (human γ4) monoclonal antibody in humans. Cancer Res 1991; 51: 5461–6

    PubMed  Google Scholar 

  30. Hale G, Dyer MJS, Clark MR, Phillips JM, Marcus R, Riechmann L, Winter G, Waldmann H. Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody CAMPATH-1H. The Lancet 1988; ii: 1394–9.

    Google Scholar 

  31. Brown PS, Parenteau GL, Dirbas FM, Garsia RJ, Goldman CK, Bukowski MA, Junghans RP, Queen C, Hakimi J, Benjamin WR, Clark RE, Waldmann TA. Anti-Tac-H, a humanized antibody to the interleukin 2 receptor, prolongs primate cardiac allograft survival. Proc Natl Acad Sci USA 1991; 88: 2663–7.

    PubMed  Google Scholar 

  32. Hakimi J, Chizzonite R, Luke DR, Familetti PC, Bailon P, Kondas JA, Pilson RS, Lin P, Weber DV, Spence C, Mondini LJ, Tsien WH, Levin JL, Gallati VH, Korn L, Waldmann TA, Queen C, Benjamin WR. Reduced immunogenicity and improved pharmacokinetics of humanized anti-Tac in cynomolgus monkey. J Immunol 1991; 147: 1352–9.

    PubMed  Google Scholar 

  33. Solomon A, Waldmann T, Fahey JL. Metabolism of normal 6.6 S γ-globulin in normal subjects and in patients with macroglobulinemia and multiple myeloma. J Lab Clin Med 1963; 62: 1–17.

    PubMed  Google Scholar 

  34. Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970; 49: 673–80.

    PubMed  Google Scholar 

  35. Intravenous gammaglobulin for immunodeficiency: report from the European Group for Immunodeficiencies (EGID). Clin exp Immunol 1986; 65: 683–90.

    Google Scholar 

  36. Hagenbeek A, Brummelhuis HGJ, Donkers A, Dumas AM, Haaft A, Schaap BJP, Sizoo W, Löwenberg B. Rapid clearance of cytomegalovirus-specific IgG after repeated intravenous infusions of human immunoglobulin into allogeneic bone marrow transplant recipients. J Inf Dis 1987; 155: 897–902.

    Google Scholar 

  37. Bosi A, de Majo E, Guidi S, Parri F, Sacchardi R, Vannucchi AM, Fanci R, Ferrini PR. Kinetics of anti-CMV antibodies after administration of intravenous immunoglobulins to bone marrow transplant recipients. Haematologica 1990; 75: 109–12.

    PubMed  Google Scholar 

  38. Aulitzky WE, Schulz TE, Tilg H, Niederwieser D, Larcher K, Östberg L, Scriba M, Martindale J, Stern AC, Grass P, Mach M, Dierich MP, Huber C. Human monoclonal antibodies neutralizing cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone marrow transplant recipients. J Inf Dis 1991; 163: 1344–7.

    Google Scholar 

  39. Rand KH, Houck H, Ganju A, Babington RG, Elfenbein GJ. Pharmacokinetics of cytomegalovirus specific IgG antibodies following intravenous immunoglobulin in bone marrow transplant patients. Bone Marrow Transpl 1989; 4: 679–83.

    Google Scholar 

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Authors and Affiliations

  1. Swiss National Center for Retroviruses, Institute of Medical Virology, University of Zürich, Zürich, Switzerland

    J. Schüpbach

  2. Division of Infectious Diseases, Department of Medicine, University Hospital Zürich, Switzerland

    H. Günthard, P. Gowland & R. Lüthy

  3. Tanox Biosystems, Inc., 10301 Stella Link, 77025, Houston, TX, USA

    M. S. C. Fung, R. -S. Liou, W. Gordon, N. T. Chang & T. W. Chang

  4. Pharmaceuticals Division, Ciba-Geigy Limited, Basle, Switzerland

    L. Botta, D. Gygax & D. G. Braun

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  1. J. Schüpbach
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  2. H. Günthard
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  3. M. S. C. Fung
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  4. R. -S. Liou
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  5. L. Botta
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  6. P. Gowland
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  7. W. Gordon
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  8. D. Gygax
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  9. N. T. Chang
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  10. T. W. Chang
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Schüpbach, J., Günthard, H., Fung, M.S.C. et al. Pharmacokinetics of an HIV-1 gp120-specific chimeric antibody in patients with HIV-1 disease. Biotherapy 6, 205–215 (1993). https://doi.org/10.1007/BF01878082

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  • DOI: https://doi.org/10.1007/BF01878082

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