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Steven Weinheimer - One of the best experts on this subject based on the ideXlab platform.
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efficacy pharmacokinetics and safety over 48 weeks with Ibalizumab based therapy in treatment experienced adults infected with hiv 1 a phase 2a study
Journal of Acquired Immune Deficiency Syndromes, 2021Co-Authors: Joseph C Gathe, Steven Weinheimer, Robin L Hardwicke, Fernando Garcia, Stanley T Lewis, Brandon R CashAbstract:ABSTRACT Ibalizumab, a humanized monoclonal antibody targeting CD4, blocks HIV-1 entry into cells and is the first FDA-approved long-acting agent for HIV-1 treatment. In this Phase 2a study, 82 HIV-infected adults failing antiretroviral therapy were assigned an individually optimized background regimen (OBR) and randomized 1:1:1 to Arm A (15 mg/kg Ibalizumab q2wk), Arm B (10 mg/kg weekly for 9 weeks, then q2wk), or placebo. Subjects with an inadequate response at Week 16 were permitted to cross over to a new OBR plus 15 mg/kg Ibalizumab q2wk. At Week 16, viral load (VL) reduction was significantly greater than placebo (0.26 log10) in Arms A (1.07 log10; p=0.002) and B (1.33 log10; p<0.001); CD4+ T cell counts increased significantly in Arm A. After Week 16, 11/27 (Arm B) and 19/27 (placebo) subjects crossed over to OBR plus 15 mg/kg Ibalizumab; 8/28 in Arm A initiated a new OBR. Ibalizumab treatment resulted in VL reduction at Week 24 (-0.77 and -1.19 log10 for Arms A and B, respectively, versus -0.32 log10 for placebo) and 48 Weeks (-0.54 and -0.77 versus -0.22 log10). Compared to placebo, VL differences were statistically significant for Arm B at Week 24 (p=0.001) and Week 48 (p=0.027). CD4+ T cell counts increased significantly by Week 48 in both Arm A and Arm B, relative to placebo. No Ibalizumab-related serious adverse events were reported. The durable antiviral activity and tolerability of Ibalizumab support its use in treating individuals harboring multidrug-resistant HIV-1.
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Efficacy, pharmacokinetics and safety over 48 weeks with Ibalizumab-based therapy in treatment-experienced adults infected with HIV-1: A Phase 2a study.
Journal of acquired immune deficiency syndromes (1999), 2021Co-Authors: Joseph C Gathe, Steven Weinheimer, Robin L Hardwicke, Fernando Garcia, Stanley T Lewis, R Brandon CashAbstract:ABSTRACT Ibalizumab, a humanized monoclonal antibody targeting CD4, blocks HIV-1 entry into cells and is the first FDA-approved long-acting agent for HIV-1 treatment. In this Phase 2a study, 82 HIV-infected adults failing antiretroviral therapy were assigned an individually optimized background regimen (OBR) and randomized 1:1:1 to Arm A (15 mg/kg Ibalizumab q2wk), Arm B (10 mg/kg weekly for 9 weeks, then q2wk), or placebo. Subjects with an inadequate response at Week 16 were permitted to cross over to a new OBR plus 15 mg/kg Ibalizumab q2wk. At Week 16, viral load (VL) reduction was significantly greater than placebo (0.26 log10) in Arms A (1.07 log10; p=0.002) and B (1.33 log10; p
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1027. Long-Term Efficacy, Safety, and Durability of Ibalizumab-Based Regimens in Subgroup of TMB-202 Participants
Open Forum Infectious Diseases, 2020Co-Authors: William J. Towner, Steven Weinheimer, Edwin Dejesus, Shannon Schrader, Jerome De Vente, Colleen S. Mcgary, Mohammed Zogheib, Pedro MesquitaAbstract:Abstract Background Third line antiretroviral regimens have been associated with suboptimal virologic suppression, due to drug cross-resistance and regimen complexity. Yet, in treatment-experienced (TE) HIV patients, ART durability is essential for preventing further resistance and decreasing HIV-associated morbidity and mortality. Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved to treat multi-drug resistant (MDR) HIV, may support regimen durability given its directly observed administration. We analyzed the safety, efficacy, and durability of response in 12 patients who started IBA in a Phase 2b study. Methods In TMB-202, 113 patients with MDR HIV received either 2000 mg IBA every 4 weeks (n=54) or 800 mg IBA every 2 weeks (n=59) for 24 weeks with an optimized background regimen (OBR). Of 96 patients who completed TMB-202, 56 transferred into an investigator-sponsored investigational new drug protocol and 12 later moved onto an expanded access protocol, TMB-311, where efficacy and safety were monitored until IBA was commercially available (approval 2018). Results Baseline median viral load (VL) and CD4 count for the 12 patients were 4.4 log10 copies/mL (c/mL) and 135 cells/mL, respectively. The median duration of HIV infection was 22 years (range 18-25). At the completion of TMB-202 11/12 achieved virologic suppression (VL < 200 c/mL) and 8/12 had VL < 50 c/mL. All 12 patients were suppressed (VL < 50 c/mL) at their last TMB-311 visit. Patients gained an average of 99 CD4 cells/mL relative to baseline. There were no treatment-emergent adverse events (TEAE) or therapy discontinuations related to IBA during follow-up. Two patients died from unrelated causes. Overall, the 12 patients remained on IBA for an average of 8.9 years (range 8-9.5), during which 8/12 did not require addition of new ARVs to their OBR to maintain suppression. Figure 1: duration of Ibalizumab-based regimen is displayed for the 12 patients. Grey bars represent patients with no addition of new ARVs to OBR. Black bars represent patients with an addition to OBR. Asterisks represent addition of ritonavir only. Conclusion Data from 12 patients who received IBA for an average of 9 years validate the long-term efficacy and safety of IBA in TE patients. Importantly, for most patients, the durability of virologic response was maintained with minimal adjustments to the OBR. Altogether, these data demonstrate the contribution of IBA towards durable viral suppression in TE HIV patients with limited therapeutic options. Disclosures William Towner, MD, Dynavax (Research Grant or Support)Gilead (Grant/Research Support)Merck (Research Grant or Support)Tai Med (Research Grant or Support)ViiV (Research Grant or Support) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member) Colleen McGary, PhD, Theratechnologies (Employee) Mohammed Zogheib, PharmD, MPH, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)
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1008. Disease Severity Impact on Long-Term Virologic Response to Ibalizumab in Expanded Access Protocol (TMB-311)
Open Forum Infectious Diseases, 2020Co-Authors: Princy Kumar, Steven Weinheimer, R Brandon Cash, Jason Leider, Jihad Slim, Graeme Moyle, Maurice Leonard, Pedro MesquitaAbstract:Abstract Background The principal goal of antiretroviral therapy (ART) is durable suppression of HIV RNA. In treatment-experienced (TE) patients, ongoing viremia can lead to further accumulation of drug resistance, increased morbidity and mortality. ART efficacy often depends on HIV disease severity; therefore, we sought to assess its impact on long-term virologic suppression in patients treated with Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved for multi-drug resistant (MDR) HIV-1 treatment. Methods In TMB-301, a Phase 3 study, 40 TE patients with viral load (VL) >1000 copies/mL (c/mL) received an intravenous (IV) loading dose of IBA (2000mg) followed by maintenance doses (800mg IV) every 2 weeks combined with an optimized background regimen. Patients who completed TMB-301 in the US (n=27) continued to an expanded access protocol TMB-311. To determine the impact of baseline (BL) disease on long-term virologic response, we conducted an on-treatment analysis stratified by BL VL and CD4 count up to week 96. Differences in the proportion of suppressed (< 50 c/mL) individuals among the strata were assessed by Fisher’s exact test. Results Median BL VL and CD4 count were 35,350 c/mL and 73 cells/mL, respectively. The number of patients in the VL strata were 11, 17 and 12 for VL < 10,000, 10,000-70,000, and >70,000 c/mL, respectively. There were 12, 10, 5 and 13 patients in the subgroups with CD4 count < 10, 10-100, >100-200 and >200 cells/µL. Population disease severity was reflected by four deaths (unrelated to study drug). Overall, the proportion of suppressed patients increased from 55% at week 24 (n=31) to 75% for patients remaining on treatment for 96 weeks (n=20). Median VL decrease was 2.9 log10 c/mL. Notably, no statistically significant differences were found across groups. Among patients with advanced HIV disease, 66.7% with CD4 count < 10 cells/mL and 71.4% with VL >70,000 c/mL at BL remained fully suppressed at week 96. Conclusion In TE patients with advanced HIV disease, maximal viral suppression with IBA was observed regardless of BL CD4 or VL strata if patients remained on treatment. This demonstrates that TE patients across the spectrum of HIV disease, can achieve viral suppression by using drugs with a new mechanism of action. Disclosures Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Jason Leider, MD, PhD, THERA (Speaker’s Bureau) Jihad Slim, MD, Abbvie (Speaker’s Bureau)Gilead (Speaker’s Bureau)Jansen (Speaker’s Bureau)Merck (Speaker’s Bureau)ViiV (Speaker’s Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Maurice Leonard, PhD, Theratechnologies Europe Ltd (Employee, Shareholder) R Brandon Cash, PharmD, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)
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Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1.
The New England journal of medicine, 2018Co-Authors: Brinda Emu, Steven Weinheimer, Jeffrey Fessel, Shannon Schrader, Princy Kumar, Gary Richmond, Sandra Win, Christian Marsolais, Stanley LewisAbstract:Abstract Background Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4. Methods In this single-group,...
Stanley Lewis - One of the best experts on this subject based on the ideXlab platform.
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Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1.
The New England journal of medicine, 2018Co-Authors: Brinda Emu, Steven Weinheimer, Jeffrey Fessel, Shannon Schrader, Princy Kumar, Gary Richmond, Sandra Win, Christian Marsolais, Stanley LewisAbstract:Abstract Background Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4. Methods In this single-group,...
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Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1
Open Forum Infectious Diseases, 2017Co-Authors: Brinda Emu, Steven Weinheimer, Shannon Schrader, Princy Kumar, Gary Richmond, Sandra Win, Christian Marsolais, W. Jeffery Fessel, Stanley LewisAbstract:Abstract Background Management of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment. Methods TMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks. Results A total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL <50 copies/ml and 17 (63%) patients had VL < 200 copies/ml. All 15 patients with VL < 50 copies/ml at Week 24 maintained viral suppression to Week 48. Conclusion IBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients. Disclosures B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner
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The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment
Antiviral research, 2011Co-Authors: W. Jeffrey Fessel, Steven Weinheimer, Stanley Lewis, Christos J. Petropoulos, Brooke Anderson, Stephen Follansbee, Mark A. Winters, Robert W. ShaferAbstract:The availability of 24 antiretroviral (ARV) drugs within six distinct drug classes has transformed HIV-1 infection (AIDS) into a treatable chronic disease. However, the ability of HIV-1 to develop resistance to multiple classes continues to present challenges to the treatment of many ARV treatment-experienced patients. In this case report, we describe the response to Ibalizumab, an investigational CD4-binding monoclonal antibody (mAb), in a patient with advanced immunodeficiency and high-level five-class antiretroviral resistance. After starting an Ibalizumab-based salvage regimen, the patient had an approximately 4.0 log(10) reduction in viral load. An inadvertently missed infusion at week 32 led to the rapid loss of virologic response and decreased susceptibility to the remainder of the patient's salvage therapy regimen. Following the reinstitution of Ibalizumab, phenotypic and genotypic resistance to Ibalizumab was detected. Nonetheless, plasma HIV-1 RNA levels stabilized at ∼2.0 log(10) copies/ml below pre-Ibalizumab levels. Continued ARV drug development may yield additional clinical and public health benefits. This report illustrates the promise of mAbs for HIV-1 therapy in highly treatment-experienced patients. Therapeutic mAbs may also have a role in pre-exposure prophylaxis in high-risk uninfected populations and may facilitate directly observed therapy (DOT) if two or more synergistic long acting agents become available.
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Loss of asparagine-linked glycosylation sites in variable region 5 of human immunodeficiency virus type 1 envelope is associated with resistance to CD4 antibody Ibalizumab.
Journal of virology, 2011Co-Authors: Jonathan Toma, Steven Weinheimer, Eric Stawiski, Jeannette M. Whitcomb, Stanley Lewis, Christos J. Petropoulos, Wei HuangAbstract:Ibalizumab (formerly TNX-355) is a first-in-class, monoclonal antibody inhibitor of CD4-mediated human immunodeficiency type 1 (HIV-1) entry. Multiple clinical trials with HIV-infected patients have demonstrated the antiviral activity, safety, and tolerability of Ibalizumab treatment. A 9-week phase Ib study adding Ibalizumab monotherapy to failing drug regimens led to transient reductions in HIV viral loads and the evolution of HIV-1 variants with reduced susceptibility to Ibalizumab. This report characterizes these variants by comparing the phenotypic susceptibilities and envelope (env) sequences of (i) paired baseline and on-treatment virus populations, (ii) individual env clones from selected paired samples, and (iii) env clones containing site-directed mutations. Viruses with reduced susceptibility to Ibalizumab were found to exhibit reduced susceptibility to the anti-CD4 antibody RPA-T4. Conversely, susceptibility to soluble CD4, which targets the HIV-1 gp120 envelope protein, was enhanced. No changes in susceptibility to the fusion inhibitor enfuvirtide or the CCR5 antagonist maraviroc were observed. Functionally, viruses with reduced Ibalizumab susceptibility also displayed high levels of infectivity relative to those of paired baseline viruses. Individual env clones exhibiting reduced Ibalizumab susceptibility contained multiple amino acid changes in different regions relative to the paired baseline clones. In particular, clones with reduced susceptibility to Ibalizumab contained fewer potential asparagine-linked glycosylation sites (PNGSs) in variable region 5 (V5) than did paired Ibalizumab-susceptible clones. The reduction in Ibalizumab susceptibility due to the loss of V5 PNGSs was confirmed by site-directed mutagenesis. Taken together, these findings provide important insights into resistance to this new class of antiretroviral drug.
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Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults
Antimicrobial agents and chemotherapy, 2008Co-Authors: Jeffrey M. Jacobson, Daniel R. Kuritzkes, Steven Weinheimer, Eliot Godofsky, Edwin Dejesus, Jeffrey A. Larson, Stanley LewisAbstract:Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of Ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with Ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log 10 ) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to Ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to Ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4 + T-cell receptors was correlated with serum Ibalizumab concentrations. There was no evidence of CD4 + T-cell depletion in Ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, Ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with Ibalizumab in combination with standard antiretroviral treatments are warranted.
Michael S. Seaman - One of the best experts on this subject based on the ideXlab platform.
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Distinct HIV-1 Neutralization Potency Profiles of Ibalizumab-Based Bispecific Antibodies.
Journal of acquired immune deficiency syndromes (1999), 2016Co-Authors: Ruijiang Song, Michael S. Seaman, Craig S. Pace, Qing Fang, Ming Sun, Chasity D. Andrews, Neal N. PadteAbstract:BACKGROUND Preexposure prophylaxis using antiretroviral agents has been shown to effectively prevent human immunodeficiency virus type 1 (HIV-1) acquisition in high-risk populations. However, the efficacy of these regimens is highly variable, which is thought to be largely due to the varying degrees of adherence to a daily intervention in the populations. Passive immunization using broadly neutralizing antibodies (bNAbs) against HIV-1, with their relatively long half-life and favorable safety profile, could provide an alternative to daily preexposure prophylaxis. However, most bNAbs have a limited breadth, only neutralizing 70%-90% of all HIV-1 strains. METHODS To overcome the problem of limited antiviral breadth, we proposed that targeting human CD4 and HIV-1 envelope proteins simultaneously may improve virus-neutralization breadth and potency. Therefore, we constructed bispecific antibodies (biAbs) using single-chain variable fragments of anti-gp120 bNAbs fused to Ibalizumab (iMab), a humanized monoclonal antibody that binds human CD4, the primary receptor for HIV-1. RESULTS Some of our biAbs neutralized 100% of HIV-1 strains tested in vitro at clinically achievable concentrations. Distinct neutralization patterns were observed in this panel of biAbs. Those biAbs with specificity for the CD4-binding site on gp120 demonstrated 100% breadth, as well as slightly improved potency compared with iMab. In contrast, biAbs with specificity for the V1-V2 apex epitope or the V3-glycan epitope on gp120 demonstrated dramatically improved potency; some showed limited gain in neutralization breadth, whereas others (eg, PGT128-LM52 and 123-iMab) improved to 100% breadth. CONCLUSION Our data suggest that this panel of iMab-based biAbs could be used to probe the parameters for potent HIV-1 neutralization. Moreover, a few of these biAbs warrant further studies and possibly clinical development.
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Rational design and characterization of the novel, broad and potent bispecific HIV-1 neutralizing antibody iMabm36.
Journal of acquired immune deficiency syndromes (1999), 2014Co-Authors: Ming Sun, Craig S. Pace, Yaoxing Huang, Neal N. Padte, Xin Yao, Michael S. SeamanAbstract:While broadly neutralizing monoclonal antibodies (bNAbs) have always been considered potential therapeutic options for the prophylactic and treatment of HIV infection, their lack of breadth against all HIV variants has been one of the limiting factors. To provide sufficient neutralization breadth and potency against diverse viruses, including neutralization escape variants, strategies to combine different bNAbs have been explored recently. We rationally designed and engineered a novel bispecific HIV-1 neutralizing antibody (bibNAb), iMabm36, for high potency and breadth against HIV. iMabm36 is composed of the anti-CD4 Ab Ibalizumab (iMab) linked to two copies of the single-domain Ab m36 which targets a highly conserved CD4-induced epitope. iMabm36 neutralizes a majority of a large, multi-clade panel of pseudoviruses (96%, n=118) at an IC50 concentration of less than 10 μg/mL, with 83% neutralized at an IC50 concentration of less than 0.1μg/ml. In addition, iMabm36 neutralizes six replication-competent transmitted-founder viruses to 100% inhibition at a concentration of less than 0.1μg/ml in a PBMC-based neutralizing assay. Mechanistically, improved antiviral activity of iMabm36 is dependent on both CD4 binding activity of iMab component and CD4i binding activity of the m36 component. After characterizing viral resistance to iMabm36 neutralization was due to mutations residing in the bridging sheet of gp120, an optimized m36 variant was engineered that, when fused to iMab, improved antiviral activity significantly. Together inter-dependency of this dual mechanism of action enables iMabm36 to potently inhibit HIV-1 entry. These results demonstrate that mechanistic-based design of bibNAbs could generate potential preventive and therapeutic candidates for HIV/AIDS.
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Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1–neutralizing activity
Nature Biotechnology, 2013Co-Authors: Ruijiang Song, Deena A. Oren, David Franco, Michael S. SeamanAbstract:Ibalizumab is a humanized monoclonal antibody that binds human CD4—a key receptor for HIV—and blocks HIV-1 infection. However, HIV-1 strains with mutations resulting in loss of an N-linked glycan from the V5 loop of the envelope glycoprotein gp120 are resistant to Ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the Ibalizumab light chain, perhaps causing steric hindrance that disrupts viral entry. If this void contributes to HIV-1 resistance to Ibalizumab, we reasoned that 'refilling' it by engineering an N-linked glycan into the Ibalizumab light chain at a position spatially proximal to gp120 V5 may restore susceptibility to Ibalizumab. Indeed, one such Ibalizumab variant neutralized 100% of 118 diverse HIV-1 strains tested in vitro , including 10 strains resistant to parental Ibalizumab. These findings demonstrate that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially enhance its activity. Strategic insertion of an N-linked glycan into the variable domain of an antibody improves its ability to inhibit HIV-1 infection.
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Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity
Nature biotechnology, 2013Co-Authors: Ruijiang Song, Deena A. Oren, David Franco, Michael S. SeamanAbstract:Ibalizumab is a humanized monoclonal antibody that binds human CD4--a key receptor for HIV--and blocks HIV-1 infection. However, HIV-1 strains with mutations resulting in loss of an N-linked glycan from the V5 loop of the envelope glycoprotein gp120 are resistant to Ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the Ibalizumab light chain, perhaps causing steric hindrance that disrupts viral entry. If this void contributes to HIV-1 resistance to Ibalizumab, we reasoned that 'refilling' it by engineering an N-linked glycan into the Ibalizumab light chain at a position spatially proximal to gp120 V5 may restore susceptibility to Ibalizumab. Indeed, one such Ibalizumab variant neutralized 100% of 118 diverse HIV-1 strains tested in vitro, including 10 strains resistant to parental Ibalizumab. These findings demonstrate that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially enhance its activity.
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Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Craig S. Pace, Ruijiang Song, Deena A. Oren, David Franco, Chasity D. Andrews, Christina Ochsenbauer, Michael S. SeamanAbstract:In the absence of an effective HIV-1 vaccine, passive immunization using broadly neutralizing Abs or Ab-like molecules could provide an alternative to the daily administration of oral antiretroviral agents that has recently shown promise as preexposure prophylaxis. Currently, no single broadly neutralizing Ab (bNAb) or combination of bNAbs neutralizes all HIV-1 strains at practically achievable concentrations in vivo. To address this problem, we created bispecific Abs that combine the HIV-1 inhibitory activity of Ibalizumab (iMab), a humanized mAb directed to domain 2 of human CD4, with that of anti-gp120 bNAbs. These bispecific bNAbs (BibNAbs) exploit iMab’s potent anti–HIV-1 activity and demonstrated clinical efficacy and safety to anchor and thereby concentrate a second broadly neutralizing agent at the site of viral entry. Two BibNabs, PG9-iMab and PG16-iMab, exhibit exceptional breadth and potency, neutralizing 100% of the 118 viruses tested at low picomolar concentrations, including viruses resistant to both parental mAbs. The enhanced potency of these BibNAbs was entirely dependent on CD4 anchoring, not on membrane anchoring per se, and required optimal Ab geometry and linker length. We propose that iMab-based BibNAbs, such as PG9-iMab and PG16-iMab, are promising candidates for passive immunization to prevent HIV-1 infection.
Brinda Emu - One of the best experts on this subject based on the ideXlab platform.
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661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)
Open Forum Infectious Diseases, 2019Co-Authors: Brinda Emu, Edwin Dejesus, Jason Leider, Mezgebe Berhe, Catherine Creticos, Steve Weinheimer, Zvi CohenAbstract:Abstract Background Ibalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study. The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients. Methods Major eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0. Results Cohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels <50 copies/mL. Of 17 patients with a VL assessment at Week 48, 8 (47%) achieved <50 copies/mL. Seven patients did not have a Week 48 endpoint because they withdrew from the study to receive commercial IBA. At both time points, the median change in VL from Baseline was -2.6 log10 copies/mL. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (24%), headache (21%), and nausea, cough, rash, and fatigue (16% each). No injection site reactions related to IBA were reported. Most events were mild; 9 patients reported Grade ≥3 TEAEs. Two events were fatal (sepsis and cardiac arrest); neither related to IBA. One event of immune reconstitution inflammatory syndrome was reported and considered possibly related to IBA. Conclusion Results from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA. Disclosures All authors: No reported disclosures.
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Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1.
The New England journal of medicine, 2018Co-Authors: Brinda Emu, Steven Weinheimer, Jeffrey Fessel, Shannon Schrader, Princy Kumar, Gary Richmond, Sandra Win, Christian Marsolais, Stanley LewisAbstract:Abstract Background Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4. Methods In this single-group,...
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Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1
Open Forum Infectious Diseases, 2017Co-Authors: Brinda Emu, Steven Weinheimer, Shannon Schrader, Princy Kumar, Gary Richmond, Sandra Win, Christian Marsolais, W. Jeffery Fessel, Stanley LewisAbstract:Abstract Background Management of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment. Methods TMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks. Results A total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL <50 copies/ml and 17 (63%) patients had VL < 200 copies/ml. All 15 patients with VL < 50 copies/ml at Week 24 maintained viral suppression to Week 48. Conclusion IBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients. Disclosures B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner
Edwin Dejesus - One of the best experts on this subject based on the ideXlab platform.
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1027. Long-Term Efficacy, Safety, and Durability of Ibalizumab-Based Regimens in Subgroup of TMB-202 Participants
Open Forum Infectious Diseases, 2020Co-Authors: William J. Towner, Steven Weinheimer, Edwin Dejesus, Shannon Schrader, Jerome De Vente, Colleen S. Mcgary, Mohammed Zogheib, Pedro MesquitaAbstract:Abstract Background Third line antiretroviral regimens have been associated with suboptimal virologic suppression, due to drug cross-resistance and regimen complexity. Yet, in treatment-experienced (TE) HIV patients, ART durability is essential for preventing further resistance and decreasing HIV-associated morbidity and mortality. Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved to treat multi-drug resistant (MDR) HIV, may support regimen durability given its directly observed administration. We analyzed the safety, efficacy, and durability of response in 12 patients who started IBA in a Phase 2b study. Methods In TMB-202, 113 patients with MDR HIV received either 2000 mg IBA every 4 weeks (n=54) or 800 mg IBA every 2 weeks (n=59) for 24 weeks with an optimized background regimen (OBR). Of 96 patients who completed TMB-202, 56 transferred into an investigator-sponsored investigational new drug protocol and 12 later moved onto an expanded access protocol, TMB-311, where efficacy and safety were monitored until IBA was commercially available (approval 2018). Results Baseline median viral load (VL) and CD4 count for the 12 patients were 4.4 log10 copies/mL (c/mL) and 135 cells/mL, respectively. The median duration of HIV infection was 22 years (range 18-25). At the completion of TMB-202 11/12 achieved virologic suppression (VL < 200 c/mL) and 8/12 had VL < 50 c/mL. All 12 patients were suppressed (VL < 50 c/mL) at their last TMB-311 visit. Patients gained an average of 99 CD4 cells/mL relative to baseline. There were no treatment-emergent adverse events (TEAE) or therapy discontinuations related to IBA during follow-up. Two patients died from unrelated causes. Overall, the 12 patients remained on IBA for an average of 8.9 years (range 8-9.5), during which 8/12 did not require addition of new ARVs to their OBR to maintain suppression. Figure 1: duration of Ibalizumab-based regimen is displayed for the 12 patients. Grey bars represent patients with no addition of new ARVs to OBR. Black bars represent patients with an addition to OBR. Asterisks represent addition of ritonavir only. Conclusion Data from 12 patients who received IBA for an average of 9 years validate the long-term efficacy and safety of IBA in TE patients. Importantly, for most patients, the durability of virologic response was maintained with minimal adjustments to the OBR. Altogether, these data demonstrate the contribution of IBA towards durable viral suppression in TE HIV patients with limited therapeutic options. Disclosures William Towner, MD, Dynavax (Research Grant or Support)Gilead (Grant/Research Support)Merck (Research Grant or Support)Tai Med (Research Grant or Support)ViiV (Research Grant or Support) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member) Colleen McGary, PhD, Theratechnologies (Employee) Mohammed Zogheib, PharmD, MPH, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)
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661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)
Open Forum Infectious Diseases, 2019Co-Authors: Brinda Emu, Edwin Dejesus, Jason Leider, Mezgebe Berhe, Catherine Creticos, Steve Weinheimer, Zvi CohenAbstract:Abstract Background Ibalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study. The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients. Methods Major eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0. Results Cohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels <50 copies/mL. Of 17 patients with a VL assessment at Week 48, 8 (47%) achieved <50 copies/mL. Seven patients did not have a Week 48 endpoint because they withdrew from the study to receive commercial IBA. At both time points, the median change in VL from Baseline was -2.6 log10 copies/mL. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (24%), headache (21%), and nausea, cough, rash, and fatigue (16% each). No injection site reactions related to IBA were reported. Most events were mild; 9 patients reported Grade ≥3 TEAEs. Two events were fatal (sepsis and cardiac arrest); neither related to IBA. One event of immune reconstitution inflammatory syndrome was reported and considered possibly related to IBA. Conclusion Results from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA. Disclosures All authors: No reported disclosures.
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Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults
Antimicrobial agents and chemotherapy, 2008Co-Authors: Jeffrey M. Jacobson, Daniel R. Kuritzkes, Steven Weinheimer, Eliot Godofsky, Edwin Dejesus, Jeffrey A. Larson, Stanley LewisAbstract:Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of Ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with Ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log 10 ) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to Ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to Ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4 + T-cell receptors was correlated with serum Ibalizumab concentrations. There was no evidence of CD4 + T-cell depletion in Ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, Ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with Ibalizumab in combination with standard antiretroviral treatments are warranted.
