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|TMB-365/TMB-380 (TMB-365 and TMB-380 combination)||
TMB-365/TMB-380 (TMB-365 and TMB-380 combination)
TMB-380 (VRC07-523LS) is the new generation of highly potent and broadly neutralizing HIV-1 antibody, which is derived from VRC07, a heavy chain somatic variant of the broadly neutralizing antibody VRC01 from HIV+ patient. Like the progenitor antibody VRC07 and VRC01, TMB-380 targets the CD4 binding site on the HIV-1 envelope glycoprotein gp120 . In vivo and in vitro studies showed that monoclonal antibody (mAb) VRC07, particularly its variant TMB-380, neutralized 96% of cross-clades viruses tested and was 5-8 times more potent than VRC01, and protected macaques against SHIV challenge at a 5-fold lower concentration than VRC01 in protecting macaques passively transferred with MAb prior to SHIV challenge, and the presence of mutations in Fc displays a 2-3 fold increase in plasma half-life .
In phase 1a clinical study results suggest that TMB-380 is safe and well-tolerated at all doses (1, 5, 20 and 40 mpk) and routes (IV and SC) in healthy adults. TMB-380 rapidly achieved concentrations greater than 10 mg/mL following 5 mg/kg SC administration. The overall compartmental half-life (t1/2) of TMB-380 is currently estimated to be 33±10 days. The potent neutralizing activity, breadth, and extended half-life of TMB-380 make this antibody a leading candidate for inclusion in HIV-1 prevention and therapeutic strategies [2, 3]. The clinical study NCT02840474 is the head-to-head comparison study of the monoclonal antibodies TMB-380 (VRC07-523LS) and VRC01LS in HIV-infected adults and the results showed both VRC01LS and TMB-380 were safe and well-tolerated. Seven days after an infusion of the antibodies, fewer than half of the people given VRC01-LS had a viral load reduction of more than 0.5 logs (a threefold reduction); but TMB-380 recipients had a viral load reduction of more than 1.2 logs (a 16-fold reduction) [4, 5].
TaiMed has a non-exclusive licensing agreement of TMB-380 from the National Institute Allergy and Infectious Diseases (NIAID) to develop combination of TMB-380 and TaiMed own monoclonal HIV antibodies for treatment use. A combination therapy of TMB-380 and TaiMed own antibody is under evaluation and development.
Dual Antibody Combination of TMB-365 with TMB-380
With broad efficacy over clades of prevalent HIV-1 variants and the long in vivo lifetimes or PK half-life, long acting, of TMB-365 and TMB-380, the dual antibody combination of TMB-365 with TMB-380, like their peers, also dual antibody combination 3BNC117 and 10-1074, are approached for HIV-1 therapy and/or prophylaxis purposes. [6, 7, 8] The TMB-365 and TMB-380 combination is designated for the treatment of HIV-1 in virologically suppressed patients. [9, 10]
Clinical trial for the combination of TMB-365 and TMB-380
Based on the available data, both TMB-365 and TMB-380 have superior antiviral activities with no safety concerns. The pharmacokinetic profiles of both antibodies indicate the potential of bi-monthly or quarterly dosing. By combining these two antibodies, the combination of TMB-380 and TMB-365 takes advantage of complementary mechanisms for inhibiting HIV entry. TaiMed has submitted an IND application to US FDA for the combination of TMB-365 and TMB-380.
A phase 1b/2a clinical trial with adaptive design was proposed for viral-suppressed HIV-1 patients. The study will investigate the safety and efficacy of the combination at different dose levels every 8 or 12 weeks.
2022: Initiation of a phase-1b/2a clinical trial for the combination of TMB-365 and TMB-380
- “VRC07-523 Info – Search Antibody Database” in HIV Databases operated by Triad national Security, LLC for National Nuclear Security Administration of US Department of Energy (DoE) and funded by US National Laboratory of Las Alamos, US National Institutes of Health (US-NIH), and US Department of Health and Human Services (US-HHS).
- “VRC 605: A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS) Administered Intravenously or Subcutaneously to Healthy Adults.” Conducted and funded by National Institutes of Health Clinical Center (NIH-CC), and National Institute of Allergy and Infectious Diseases (NIAID).
- Martin R. Gaudinski et al., “A Phase I Dose-Escalation Study of Monoclonal Antibody VRC07-523LS in Healthy Adults.” Conference on Retroviruses and Opportunistic Infections” CROI 2018, Abstract Number: 1061 (Poster 022618).
- “IAS 2019: FIRST TRIAL RESULTS OF NEW IMMUNE-MODULATING DRUGS PRESENTED IN MEXICO CITY.” - EATG REPORTED.
- Chen G et al. “Safety and virologic effect of the HIV-1 broadly neutralizing antibodies, VRC01LS or VRC07-523LS, administered to HIV-infected adults in a phase 1 clinical trial.” IAS2019 conference, Mexico City. Abstract WEAA0305LB. 2019.
- Cohen YZ et al., “Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study.” PLOS ONE (2019).
- Julio CC et al., “Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Primary African Isolates” J. Virol. (2021) 95: e01909-20.
- Wagh K et al., “Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection” PLOS Pathogens (2016).
- ViiV Healthcare Press and News Release: ViiV Healthcare to Present New Long-term Findings from Its Innovative 2-Drug and Long-Acting HIV Medicines Portfolio at CROI 2022. 07 FEB, 2022.
- ViiV Healthcare Press and News Release: ViiV Healthcare Announced US FDA Approval of CABENUVA (CABOTEGARVIR, RILPIVIRINE) for Use Every Two Months, Expanding the Label of The First and Only Complete Long Acting HIV Treatment. 01 FEB. 2022.