Tebentafusp is a bispecific fusion protein, comprised of a T cell receptor (TCR; targeting domain) fused to an antibody fragment targeting CD3 (cluster of differentiation 3; effector domain). The TCR end binds with high affinity to a gp100 peptide presented by human leukocyte antigen – A*02:01 (HLA-A*02:01) on the cell surface of uveal melanoma tumour cells, and the effector domain binds to the CD3 receptor on the polyclonal T cell.
An immune synapse is formed when the TCR targeting domain of tebentafusp binds to uveal melanoma cells and the CD3 effector domain binds to polyclonal T cells. This immune synapse results in redirection and activation of polyclonal T cells regardless of their native TCR specificity. Tebentafusp activated polyclonal T cells release inflammatory cytokines and cytolytic proteins, which result in direct lysis of uveal melanoma tumour cells.
Transient and clinically nonsignificant reduction in lymphocyte counts in blood was observed after treatment with tebentafusp. Lymphocytes decreased the day after the first 3 doses and returned to baseline prior to subsequent doses. After treatment with tebentafusp, transient increases in serum levels of proinflammatory cytokines and chemokines were observed in samples collected after the first three doses. Peak levels were observed between 8 to 24 hours after treatment with tebentafusp and levels returned to baseline prior to subsequent doses.
The pharmacokinetics of tebentafusp appear linear and dose proportional over a dose range of 20 mcg to 68 mcg. Following weekly intravenous infusion in metastatic uveal melanoma patients, the maximum plasma concentrations (Cmax) reached 4.2 ng/mL – 13.7 ng/mL immediately at the end of infusion (T=0.5 hours). No accumulation was observed with a weekly dosing regimen at the target therapeutic doses.
Tebentafusp did not distribute extensively and displayed a volume of distribution comparable to blood volume (5.25 L).
The metabolic pathway of tebentafusp has not been characterised. Like other protein therapeutics, tebentafusp is expected to be degraded into small peptides and amino acids via catabolic pathways.
The excretion of tebentafusp is not fully characterised. Based on its molecular size that is close to the glomerular filtration size exclusion threshold, small amounts of tebentafusp may be excreted in the urine.
Following administration of tebentafusp in metastatic uveal melanoma patients the estimated systemic clearance was 4.29 L/d, with a terminal half-life of 6 to 8 hours.
Population pharmacokinetic analysis indicated that there was no significant effect of weight (43 to 163 kg), gender, race, and age (23 to 91 years) on tebentafusp clearance.
No formal pharmacokinetic studies of tebentafusp have been conducted in patients with renal impairment.
No impact on safety or efficacy parameters was identified in patients with mild (creatinine clearance [CrCL] ranging 60 to 89 mL/min) to moderate (CrCL ranging 30 to 59 mL/min) renal impairment and no dose adjustments are recommended. There are limited data from patients (<5%) with moderate renal impairment and there is no information available from patients with severe renal impairment (CrCL <30 mL/min).
No formal pharmacokinetic studies of tebentafusp have been conducted in patients with hepatic impairment. Population PK analyses demonstrated that baseline and on treatment ALT/AST elevations did not impact tebentafusp pharmacokinetics. No dose adjustments based on ALT/AST levels are recommended.
Tebentafusp is a human--specific protein and there are no relevant animal species in which nonclinical toxicology of tebentafusp could be tested.
No carcinogenicity, genotoxicity, or developmental and reproductive toxicity studies have been conducted with tebentafusp.
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