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Antiviral Research 29 (1996) 73 75
0
Antiviral Research
Short communication
CMV retinitis: ganciclovir/monoclonal antibody Richard
B. P o l l a r d
The University of Texas Medical Branch, Galveston, TX 77555-0882, USA
Keywords: Cytomegalovirus; Retinitis; Ganciclovir; Foscarnet
Cytomegalovirus infection remains a major clinical problem in patients with AIDS and in certain transplant situations. The most common manifestation of Cytomegalovirus (CMV) infection in patients with AIDS is retinitis which occurs in up to 20-30%. Individuals affected mostly include those with severe immunosuppression with C D 4 counts less then 50. There are two approved therapies for treatment of acute retinitis including ganciclovir and foscarnet, both of which are given intravenously for a 2 week induction and then continued intravenously as long term maintenance therapy [1]. In addition, oral ganciclovir has recently been approved for use in maintenance of patients with CMV retinitis which has responded to initial intravenous therapy. The major difficulty with CMV retinitis is the development of progressive disease which occurs in essentially all patients. This occurs despite maintenance therapy with the approved drugs and is presumably due to continued virus replication at the local site. Investigations into the reason for enhanced susceptibility to CMV infections has identified depressed cell mediated immune responses to CMV in patients susceptible. Attempts to restore cellular immunity by expanding donor cytotoxic T lymphocytes that are targeted towards CMV are
preceding. This strategy which seems innovative may be inappropriate for large numbers of patients. In addition, the duration of the transplanted cell population required to restore the immune responses is not apparent. Another potential intervention that attempts to restore immunity would be the transfer of antibody to restore humoral immune responses to CMV. There have been multiple studies of polyclonal CMV antibody which to date have produced mixed results. There is evidence that polyclonal CMV antibody can protect certain seronegative transplant recipients who receive an organ from a seropositive donor. Antibody preparations have generally low levels of antibodies and specific CMV targeted antibody are difficult to prepare, requiring donation of serum from large numbers of seropositive donors; they also have the potential of being variable from lot to lot. Recent studies have identified a specific deficit in humoral immune responses to specific glycoprotein epitopes on the surface of CMV. In studies examining antibody responses to glycoproteins gB and gH, it has been determined that there is a relative deficiency of antibody to G H which occurs in patients at risk for CMV infection while high titers of antibody to gB are present even in patients susceptible to infection [2]. This raises the question whether administration of
0166-3542/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0166-3542(95)00922-2
74
R.B. Pollard / Antiviral Research 29 (1996) 73 75
specific antibody directed at an individual epitope could prove to have clinical benefit. The antibody discussed in this abstract is MSL 109 which is a specific monoclonal antibody directed at the gH glycoprotein of human CMV. This is a human monoclonal antibody which has been studied in several preliminary trials. The antibody is a human I g G l - k a p p a monoclonal antibody that has a molecular weight of ,-~ 150 000 and has been shown to have neutralizing activity against both laboratory and patient isolates in vitro. The range of sensitivity of both wild and laboratory strains are somewhere between 0.2 and 0.5 mg per ml (EDs0) [3]. In addition, when combined with either ganciclovir or foscarnet in vitro, MSL 109 is at least additive to marginally synergistic in inhibiting laboratory and wild CMV isolates [4]. The clinical development of MSL 109 has involved 2 phase I/II trials being completed. The first study was a study in patients who were CMV seropositive and shedding CMV in their urine [5]. There were several cohorts of four subjects each with one of four in each dosage cohort receiving Sandaglobulin as a control. All subjects were treated with intravenous MSL 109 or Sandagloblin every 2 weeks for 24 weeks. The dosages utilized of MSL 109 included 0.125 mg per kg, 0.5 mg per kg, 1.0 mg per kg, and 2.0 mg per kg. The MSL 109 was well tolerated and no side effects definitively attibutable to the compound were identified. The current study is a phase I/II study of patients with CMV retinitis that had been treated with induction therapy with ganciclovir or foscarnet and then received various dosages of MSL 109 as maintenance [6]. The MSL 109 was begun as close to the start of maintenance therapy as possible and different dosages of MSL 109 were utilized, including 0.25 mg per kg, 1.0 mg per kg, 2.0 mg per kg and 5.0 mg per kg. The patients included 17 patients with a m e a n C D 4 count of 32. Thirteen of the patients had D H P G as maintenance therapy, four received foscarnet. Five patients withdrew after one to seven dosages for various reasons not related to progressive retinitis. Patients in this trial received MSL 109 every 2 weeks as an IV infusion for a maximum of eight dosages (112 days). All patients were followed by ophthalmologist every 2 weeks while they received
MSL 109 and after the administration, at 4 and 8 weeks post dosing. The time to progression in the patient treated at the study sites which included Harvard University and The University of Texas at Galveston were 212 and 183 days, respectively. For the overall trial results the medium time to progression was 202 days. There was no significant clinical adverse effects observed in the trial. Serum levels of the MSL 109 suggested that all patients treated with a dose of 0.5 mg per kg had serum levels that were above the EDso of wild and laboratory strains CMV at 2 weeks post dosing (trough levels). The half life of the antibody as determined in these two preliminary studies appear to be between 14 and 16.5 days. In addition, using an anti idiotype assay to detect antibody to MSL 109, none was observed in the patients in this clinical study, nor in the phase I study in patients who were shedding CMV. The conclusion from these studies suggests that MSL is well tolerated. There appeared to be a dose related increase in both peak and trough serum levels which corresponded to the amount of MSL 1 infused. Trough levels could easily be maintained above the EDs0 of cytomegalovirus. No antibody to MSL 109 has been identified to date. Further clinical studies appear to be warranted. To follow up on these preliminary results, two clinical trials have either been recently started or are to begin. The first is A C T G 266, a randomized-masked study of placebo versus low and moderated dosage MSL 109 which will be begun at the time of induction therapy and administered every 2 weeks to patients with newly diagnosed CMV retinitis. Patients will also be receiving standard maintenance therapy. The overall objectives of this study includes determining the effect of MSL 109 on the time to progression of CMV retinitis. One hundred and sixty eight patients will be studied. To obtain additional information about the material as well as additional pharmacokinetic information, sub-studies will be conducted. To examine the rate of emergence of resistance if any to either MSL 109 or to one of two standard agents, viruses will be expanded. In addition, in a small number of patients, the ability of MSL 109 administration to induce antibody
R.B. Pollard / Antiviral Research 29 (1996) 73 75
dependent cellular cytotoxicity to CMV infected target cells will be examined. Finally, an intense examination of CMV viral load will be conducted in these studies, comparing various assay methodologies including antigenemia and PCR techniques. Another study, which will begin shortly, conducted by SOCA is a randomized Phase II/III placebo-controlled trial of ~ 300 patients which will explore one dose of MSL versus placebo in patients with newly diagnosed or recently relapsing CMV retinitis. These additional clinical studies should provide information which will be important in understanding the ultimate role of addition of virus specific monoclonal antibody to standard chemotherapy. This approach, if successful, could be utilized in other clinical situations.
[2]
[3]
[4]
[5]
[6]
References [1] SOCA in collaboration with ACTG. (1992) Mortality in
75
patients with acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N. Eng. J. Med. 326, 213-220. Rasmussen, L. et al. (1994) Deficiency in antibody response to Human Cytomegalovirus Glycoprotein gH in Human Immunodeficiency virus-infected patients at risk for Cytomegalovirus. J. Infectious Diseases 170, 673-677. Lakeman, F., Blevins, B.S., Whitley, R. and Tolpin, M. (1991) in Vitro neutralization of Cytomegalovirus (CMV) strains by a human monoclonal antibody. MSL-109. Antiviral. Res. 15 (Suppl. 1), 77. Nokta, M.A., Tolpin, M.D., Nadler, P.I. and Pollard, R.B. (1994) Human monoclonal anti-cytomegalovirus (CMV) antibody (MSL-109): Enhancement of in vitro foscarnet and ganciclovir induced inhibition of CMV replication. Antiviral. Res. 24, 17-26. Pollard, R.B., Nokta, M.A. et al. (1992) An anti-cytomegalovirus human monoclonal antibody in individuals with AIDS: A phase I/II study. Antiviral. Res. 16 (Suppl. 1), 111. Tolpin, M., Pollard, R., Tierney, M., Nokta, M., Wood, D. and Hirsch, M. (1993) Combination therapy of cytomegalovirus (CMV) retinitis with a human monoclonal antibody (SDZ MAL 109) and either ganciclovir (DHPG) or foscarnet (PFA). IXth International Conf on AIDS.
Antiviral Research 29 (1996) 73 75
0
Antiviral Research
Short communication
CMV retinitis: ganciclovir/monoclonal antibody Richard
B. P o l l a r d
The University of Texas Medical Branch, Galveston, TX 77555-0882, USA
Keywords: Cytomegalovirus; Retinitis; Ganciclovir; Foscarnet
Cytomegalovirus infection remains a major clinical problem in patients with AIDS and in certain transplant situations. The most common manifestation of Cytomegalovirus (CMV) infection in patients with AIDS is retinitis which occurs in up to 20-30%. Individuals affected mostly include those with severe immunosuppression with C D 4 counts less then 50. There are two approved therapies for treatment of acute retinitis including ganciclovir and foscarnet, both of which are given intravenously for a 2 week induction and then continued intravenously as long term maintenance therapy [1]. In addition, oral ganciclovir has recently been approved for use in maintenance of patients with CMV retinitis which has responded to initial intravenous therapy. The major difficulty with CMV retinitis is the development of progressive disease which occurs in essentially all patients. This occurs despite maintenance therapy with the approved drugs and is presumably due to continued virus replication at the local site. Investigations into the reason for enhanced susceptibility to CMV infections has identified depressed cell mediated immune responses to CMV in patients susceptible. Attempts to restore cellular immunity by expanding donor cytotoxic T lymphocytes that are targeted towards CMV are
preceding. This strategy which seems innovative may be inappropriate for large numbers of patients. In addition, the duration of the transplanted cell population required to restore the immune responses is not apparent. Another potential intervention that attempts to restore immunity would be the transfer of antibody to restore humoral immune responses to CMV. There have been multiple studies of polyclonal CMV antibody which to date have produced mixed results. There is evidence that polyclonal CMV antibody can protect certain seronegative transplant recipients who receive an organ from a seropositive donor. Antibody preparations have generally low levels of antibodies and specific CMV targeted antibody are difficult to prepare, requiring donation of serum from large numbers of seropositive donors; they also have the potential of being variable from lot to lot. Recent studies have identified a specific deficit in humoral immune responses to specific glycoprotein epitopes on the surface of CMV. In studies examining antibody responses to glycoproteins gB and gH, it has been determined that there is a relative deficiency of antibody to G H which occurs in patients at risk for CMV infection while high titers of antibody to gB are present even in patients susceptible to infection [2]. This raises the question whether administration of
0166-3542/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0166-3542(95)00922-2
74
R.B. Pollard / Antiviral Research 29 (1996) 73 75
specific antibody directed at an individual epitope could prove to have clinical benefit. The antibody discussed in this abstract is MSL 109 which is a specific monoclonal antibody directed at the gH glycoprotein of human CMV. This is a human monoclonal antibody which has been studied in several preliminary trials. The antibody is a human I g G l - k a p p a monoclonal antibody that has a molecular weight of ,-~ 150 000 and has been shown to have neutralizing activity against both laboratory and patient isolates in vitro. The range of sensitivity of both wild and laboratory strains are somewhere between 0.2 and 0.5 mg per ml (EDs0) [3]. In addition, when combined with either ganciclovir or foscarnet in vitro, MSL 109 is at least additive to marginally synergistic in inhibiting laboratory and wild CMV isolates [4]. The clinical development of MSL 109 has involved 2 phase I/II trials being completed. The first study was a study in patients who were CMV seropositive and shedding CMV in their urine [5]. There were several cohorts of four subjects each with one of four in each dosage cohort receiving Sandaglobulin as a control. All subjects were treated with intravenous MSL 109 or Sandagloblin every 2 weeks for 24 weeks. The dosages utilized of MSL 109 included 0.125 mg per kg, 0.5 mg per kg, 1.0 mg per kg, and 2.0 mg per kg. The MSL 109 was well tolerated and no side effects definitively attibutable to the compound were identified. The current study is a phase I/II study of patients with CMV retinitis that had been treated with induction therapy with ganciclovir or foscarnet and then received various dosages of MSL 109 as maintenance [6]. The MSL 109 was begun as close to the start of maintenance therapy as possible and different dosages of MSL 109 were utilized, including 0.25 mg per kg, 1.0 mg per kg, 2.0 mg per kg and 5.0 mg per kg. The patients included 17 patients with a m e a n C D 4 count of 32. Thirteen of the patients had D H P G as maintenance therapy, four received foscarnet. Five patients withdrew after one to seven dosages for various reasons not related to progressive retinitis. Patients in this trial received MSL 109 every 2 weeks as an IV infusion for a maximum of eight dosages (112 days). All patients were followed by ophthalmologist every 2 weeks while they received
MSL 109 and after the administration, at 4 and 8 weeks post dosing. The time to progression in the patient treated at the study sites which included Harvard University and The University of Texas at Galveston were 212 and 183 days, respectively. For the overall trial results the medium time to progression was 202 days. There was no significant clinical adverse effects observed in the trial. Serum levels of the MSL 109 suggested that all patients treated with a dose of 0.5 mg per kg had serum levels that were above the EDso of wild and laboratory strains CMV at 2 weeks post dosing (trough levels). The half life of the antibody as determined in these two preliminary studies appear to be between 14 and 16.5 days. In addition, using an anti idiotype assay to detect antibody to MSL 109, none was observed in the patients in this clinical study, nor in the phase I study in patients who were shedding CMV. The conclusion from these studies suggests that MSL is well tolerated. There appeared to be a dose related increase in both peak and trough serum levels which corresponded to the amount of MSL 1 infused. Trough levels could easily be maintained above the EDs0 of cytomegalovirus. No antibody to MSL 109 has been identified to date. Further clinical studies appear to be warranted. To follow up on these preliminary results, two clinical trials have either been recently started or are to begin. The first is A C T G 266, a randomized-masked study of placebo versus low and moderated dosage MSL 109 which will be begun at the time of induction therapy and administered every 2 weeks to patients with newly diagnosed CMV retinitis. Patients will also be receiving standard maintenance therapy. The overall objectives of this study includes determining the effect of MSL 109 on the time to progression of CMV retinitis. One hundred and sixty eight patients will be studied. To obtain additional information about the material as well as additional pharmacokinetic information, sub-studies will be conducted. To examine the rate of emergence of resistance if any to either MSL 109 or to one of two standard agents, viruses will be expanded. In addition, in a small number of patients, the ability of MSL 109 administration to induce antibody
R.B. Pollard / Antiviral Research 29 (1996) 73 75
dependent cellular cytotoxicity to CMV infected target cells will be examined. Finally, an intense examination of CMV viral load will be conducted in these studies, comparing various assay methodologies including antigenemia and PCR techniques. Another study, which will begin shortly, conducted by SOCA is a randomized Phase II/III placebo-controlled trial of ~ 300 patients which will explore one dose of MSL versus placebo in patients with newly diagnosed or recently relapsing CMV retinitis. These additional clinical studies should provide information which will be important in understanding the ultimate role of addition of virus specific monoclonal antibody to standard chemotherapy. This approach, if successful, could be utilized in other clinical situations.
[2]
[3]
[4]
[5]
[6]
References [1] SOCA in collaboration with ACTG. (1992) Mortality in
75
patients with acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N. Eng. J. Med. 326, 213-220. Rasmussen, L. et al. (1994) Deficiency in antibody response to Human Cytomegalovirus Glycoprotein gH in Human Immunodeficiency virus-infected patients at risk for Cytomegalovirus. J. Infectious Diseases 170, 673-677. Lakeman, F., Blevins, B.S., Whitley, R. and Tolpin, M. (1991) in Vitro neutralization of Cytomegalovirus (CMV) strains by a human monoclonal antibody. MSL-109. Antiviral. Res. 15 (Suppl. 1), 77. Nokta, M.A., Tolpin, M.D., Nadler, P.I. and Pollard, R.B. (1994) Human monoclonal anti-cytomegalovirus (CMV) antibody (MSL-109): Enhancement of in vitro foscarnet and ganciclovir induced inhibition of CMV replication. Antiviral. Res. 24, 17-26. Pollard, R.B., Nokta, M.A. et al. (1992) An anti-cytomegalovirus human monoclonal antibody in individuals with AIDS: A phase I/II study. Antiviral. Res. 16 (Suppl. 1), 111. Tolpin, M., Pollard, R., Tierney, M., Nokta, M., Wood, D. and Hirsch, M. (1993) Combination therapy of cytomegalovirus (CMV) retinitis with a human monoclonal antibody (SDZ MAL 109) and either ganciclovir (DHPG) or foscarnet (PFA). IXth International Conf on AIDS.