| Monoclonal antibody | |
|---|---|
| Type | ? |
| Clinical data | |
| Other names | RG6102 |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| UNII | |
Trontinemab (RG6102) is a monoclonal antibody developed by Roche/Genentech for the treatment of Alzheimer's disease. It is based on gantenerumab, an anti-amyloid monoclonal antibody, and uses a Brainshuttle domain to enhance its permeability through the blood-brain barrier. [1] Compared to gantenerumab, it has 50 times as much penetrance into the brain. [2] [3] [4] [5]
Trontinemab consists of the anti-amyloid mAb ganterenumab, fused with a Fab fragment that binds to human transferrin receptor 1 (TfR1) in the Fc domain. [6] The fully-human monoclonal antibody gantenerumab preferentially targets Aβ fibrils and Aβ oligomers over the monomer form (Kd: 0.6, 1.2, and 17 nM for the three forms, respectively). After binding to the Aβ, gantenerumab elicits amyloid clearance through microglia-mediated phagocytosis. [1] Gantenerumab showed some amyloid clearance in human trials, especially at high doses; however, its lower-than-expected amyloid removal capacity, its inability to slow the disease progression, even at high doses, and its side effects (including ARIA) prevent the mAb from entering clinical practice. [7]
To improve safety and efficacy, scientists tried to increase gantenerumab's ability to cross the blood-brain barrier by adding to the mAb a Fab fragment (BrainShuttle module) that binds to one of the receptors expressed on the cells that make up the BBB. The binding would then trigger the endocytosis of the mAb so that it could be transported through the cell and released to the brain. Trontinemab contains a single anti-TfR1 Fab fragment bound to the Fc region, because initial testing showed that mAbs with 2 Fab fragments were easily degraded by lysosomes and had an inferior transportation efficiency compared to mAbs with a single anti-TfR1 Fab. [8] The Fab fragment is strategically inverted to prevent an ADCC response to TfR1-expressing cells - the mAb, when the BS module binds to TfR1, assumes a position that allows the 2 anti-amyloid arms to create a clash between them and the Fc receptors of the FcγR class on the effector cells, preventing cells from engaging the Fc domain of the mAb. [9] The resulting mAb, trontinemab, has the following characteristics:
- 50 times increase in BBB penetration than the original mAb. [1]
- Even distribution throughout the brain. [1]
- Low incidence of ARIA, possibly due to the mAb entering mostly through small blood vessels, almost skipping entirely the aggregated amyloid-beta plaques on the big vessels. [10]
- Low immune reaction to TfR1-expressing cells. [9]
Trontinemab was first developed under the code name RG6102 or, as referred to by Roche/Genentech, brain-shuttle gantenerumab. Phase 1 dose-ascending study on healthy volunteers presented at AD/PD 2021 showed a half-life ranging from 3 to 6 days and a linear relationship between plasma and CSF concentration. Brain exposure, measured by CSF/plasma ratio, increased from 0.1% for normal IgG to 0.8% with brain-shuttle gantenerumab. [11] After gantenerumab failed in 2 phase III trials, Roche changed brainshuttle gantenerumab to trontinemab. [12]
Following the first-in-human study, a phase Ib/II study named BrainShuttle AD was launched. Patients enrolled in the study were randomized to a placebo group or one of the 0.2, 0.6, 1.8, or 3.6 mg/kg cohorts. The drug was initially shown to be effective at the 1.8 mg/kg dose, with the amount of amyloid-beta dropped by an average of 84 centiloids (centiloid is a scale that quantifies amyloid-PET activity in the brain measured by tracers like florbetapir (18F)) on day 84. Amyloid-beta concentration dropped below the threshold of amyloid positivity (24.1 CL) in 75% of participants. [13] Later on, the 3.6 mg/kg cohort produced results at CTAD 2024, when it cleared an average of 107 CL on day 84. [14] After combining the results of both parts 1 and 2 of the study, the highest dose group cleared a mean of 99 CL. 91% of the participants in the 3.6 mg/kg cohort were below the amyloid positivity threshold, and amyloid PET burden was reduced to below 11 CL in 72% of them. [15] In the highest dose group, there was no non-responder. [16]
Aβ depletion was early, deep, and even, with all lobes of the neocortex showing amyloid burden below 24 CL. [16] Brain regions showing rapid amyloid depletion temporarily shrank due to a large volume of amyloid being taken away. When amyloid beta had been cleared, the reduction stopped. [17] Trontinemab treatment increased Aβ42 concentration and Aβ42/40 ratio in the CSF, as well as decreased disease biomarkers, including total Tau, pTau181, neurogranin, and SNAP25 levels. [16]
As for the safety profile, the most common adverse effects were infusion-related reactions and anemia. The incidence of IRRs reduced when more aggressive premedication with steroids was used, while the incidence of anemia was attributed to frequent blood draws and was considered infrequent and mild. ARIA (both ARIA-E and ARIA-H) was uncommon, with a combined incidence rate of 4.1% in the highest dose group. [15] There was a fatal case in the 1.8 mg/kg cohort - a 78-year-old woman who had a large bleeding in her right frontal lobe on day 44. She had been considered a person with a high bleeding risk due to her screening tests showing that she had superficial siderosis and genetic factors, which are the signs of probable cerebral amyloid angiopathy. The trial's protocol was amended after her death to exclude those with superficial siderosis. [14]
In AAIC 2025, Roche announced its plans for two phase III, identically-designed trials, Trontier 1 and Trontier 2. [18]