TMB-365

The TMB-365 is an ibalizumab (TMB-355) based, IgG1-scaffold, anti-CD4 recombinant humanized monoclonal antibody used against HIV infections.  The major medication or medicament of TMB-365 is mainly focused upon treatment and prevention against HIV infections (including opportunistic infections), said therapeutic and prophylactic usages or medical application.  The TMB-365-relevant technology platforms of TMB-365 are licensed from Arron Diamond AIDS Research Center (ADARC) anchored at Rockefeller University (RU). 
   
During the clinical development of the first generation anti-CD4 humanized, recombinant monoclonal antibody, TMB-355, also ibalizumab and formerly TNX-355, for the treatment against HIV infections, the drug resistance testing showed that there is around or excess 10% of the HIV clinical isolates and strains identified to be the existing ibalizumab drug resistant mutants while ibalizumab demonstrated itself to be the outstanding highly neutralizing antibody against HIV infection in clinical setting.
 
The existent drug resistance against ibalizumab in clinical investigation was sending a call or signal of message and drawing attentions to well-known HIV research group led by Dr. David Ho, the distinguishing, leading investigator and inventor of the creative and innovative cocktail therapy against HIV, at Arron Diamond AIDS Research Center (ADARC) anchored at Rockefeller University (RU).  Through intensive efforts via internal and external collaboration with AIDS research institutions around the globe, the ADARC team decoded that the ibalizumab resistance is elicited from an unusual glycan mutation on the HIV envelop protein gp120 broadly neutralizing antibodies from HIV infected patients.  That is, if the absence of the glycan originated on HIV gp120 is existent, the mutant HIV viruses are capable of exerting the “entry” process of intact viral particle into the cell without jeopardizing the viral binding to CD4 receptor and the following process of binding to co-receptor CCR5 or CXCR4, engaging the fusion and engulfment of HIV in to the human host cell like CD4+ T lymphocytes or T cells.  In such a scenario, the presence or absence of ibalizumab as the post-attachment blocker against HIV entry will be unable to impose any impact on the HIV mutants successfully to infect the healthy human T cells.

The interactions in between the V5-glycan on HIV gp120, human CD4 receptor and monoclonal antibody ibalizumab (TMB-355)
 
With an exciting discovery on the mechanism of the ibalizumab resistance, Dr. Ho led the ADARC task force to deploy a campaign employing proprietary state-of-the-art technologies attempting to reverse the drug resistant mutants to be susceptible to an ibalizumab (iMab) based novel recombinant monoclonal antibody or antibodies.  ADARC scientists used clever concepts of reverse engineering and leading glycan engineering in parallel with their well-established understanding on AIDS research, and their expertise on iMab and antibody genetic engineering (molecular cloning and manipulations) and technologies to innovate the LM52 glycan modifications technology by genetically engineering a new glycan upon the key amino acid residue on niche domain of iMab [1]. They created the next generation of the iMab derivatives, able to not only make the iMab-resistant mutants but also the iMab-susceptible strains or isolates susceptible,  The new humanized monoclonal recombinant antibodies, TMB-365, keep excellent profile of potency similar to iMab and superior to any well-known developing or naturally existing neutralizing antibodies.  In addition, according to our current knowledge on the neutralization spectrum, the next generation iMab derivatives demonstrate superb functionalities and biological activities of susceptibility in supreme coverage of over and even much greater than 95% against existent HIV engineered lab-used constructs and naturally evolved strains and evolving isolates in clinic settings (iMab, TMB-355, shares around 75% recovery on broad neutralization tests). All these critical attributes make the next generation iMab a broadly neutralizing antibody against HIV infections, and take chance on combination with other agents, the highly active antiretroviral therapy or cocktail therapy (HAART or ART), particularly long-acting or long lasting or direct-acting antiretrovirals (ARVs), small molecular and/or biologic biomolecular entities to cover the cross-resistance, identified, existed or existing drug resistance in between each other as well.

The interaction in between the genetically glycan-engineered or -modified TMB-355 (now called TMB-365), LM52 glycan on TMB-365, human CD4 receptor and ibalizumab-resistant HIV gp120 without V5-glycan.

Broader spectrum of TMB-365 biological activity against ibalizumab-resistant HIV viruses.

Broader, wider viral coverage range and higher, greater anti-infectivity of TMB-365 (also called LM52 which is designated by ADARC) against HIV virus.

In addition to the TMB-365's characteristics on exquisite profiles on highly potent and broad neutralization against HIV infections, ADARC team again take approaches on novel iMab, said TMB-365, to overcome and improve TMB-355 limitations on clinical performance for practice in terms of pharmacokinetics (PK), pharmacodynamics (PD), bio therapeutics and dosage form.  Magnificent engineering makes use of the mutated IgG1 backbone, especially the introduction of FcR binding functions, without or with less activity on antibody-dependent cellular cytolysis (ADCC) effector function and escalating and facilitating PK/PD or biotherapeutics performance, and introducing, presenting IgG1 scaffold with evidently stable disulfide bridging and bonding in TMB-365 instead of IgG4 framework in TMB-355 for upholding and sustaining the stability of the antibody structure.  Besides, in order to conquer the known facts of high turnover rate of TMB-355 in both health and patient subjects, which is believed to be driven by the mechanism and machinery of the target or receptor (binding) mediated drug disposition or elimination (TMDD), ADARC team, once again, utilized rational design using technical engineering rationales (under patenting) on target (receptor)-binding amino acids on the surface of the antibody Fv domain, engineering ibalizumab into the novel TMB-365, pushing forth a new pipeline generation.
The end-goals are to generate ibalizumab-based antibody with  improved breadth, potency, stability and PK/PD.  That is, all exercised attributes or manipulated characters binding or bound together with one another are aimed at achieving major milestones and accomplishing key performance indices (KPIs) as well in clinic:
(1)    Higher anti-viral response rates
(2)    Greater improved viral load reductions
(3)    Decrease dose and/or decrease dosing frequency of administrations via parenteral routes. That is, achieving monthly dosing.

The first-in-human phase I trial of TMB-365 has been approved by US FDA in August, 2019 and the study is ongoing.

Phase 1 clinical trial

A phase-1 clinical trial was completed in 2021. Based on the study results, TMB-365 demonstrated a superior antiviral activity without any safety concerns. The pharmacokinetic (PK) results were better than expected and showed the potential for bi-monthly or quarterly dosing. With the promising data from the phase-1 study, TaiMed has submitted an IND application to US FDA for the combination of TMB-365 and TMB-380.

Milestones

2021: Completion of a phase-1 clinical trial.
2022: Initiation of a phase-1b/2a clinical trial for the combination of TMB-365 and TMB-380.

References

 [1] Song, R; Oren, DA and et al. Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1 –neutralizing activity.  Nature biotechnology 2013, 31; 1047.