Loncastuximab tesirine is an antibody-drug conjugate (ADC) targeting CD19. The monoclonal IgG1 kappa antibody component binds to human CD19, a transmembrane protein expressed on the surface of cells of B-lineage origin. The small molecule component is SG3199, a PBD dimer and alkylating agent.
Upon binding to CD19, loncastuximab tesirine is internalised followed by release of SG3199 via proteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death.
Higher loncastuximab tesirine exposure in Cycle 1 was associated with higher efficacy over the dose range of 0.015-0.2 mg/kg (0.1 to 1.33 times the maximum recommended dose). Higher loncastuximab tesirine exposure in Cycle 1 was associated with higher incidence of some Grade ≥2 adverse reactions, including skin and nail reactions, liver function test abnormalities and increased γ-glutamyltransferase.
At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2, loncastuximab tesirine does not cause large mean increases (i.e., >20 msec) in the QTc interval.
The exposure of loncastuximab tesirine at the approved recommended dosage in Cycle 2 and at steady state is shown in the table below. Loncastuximab tesirine steady state Cmax was 39.0% lower than the Cmax after the second dose. The time to reach steady state was approximately 15 weeks.
Loncastuximab tesirine exposure parameters:
| Time | Cmax (ng/mL) | AUCtau (ng • day/mL) |
|---|---|---|
| Cycle 2 | 2795 (36.4%) | 22,082 (46.0%) |
| Steady state | 1705 (31.6%) | 16,265 (34.9%) |
Cmax = Maximum predicted serum concentration; AUCtau = Area under curve over the dosing interval. Data presented as geometric mean and coefficient of variation (% CV)
Loncastuximab tesirine is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
The geometric mean (CV%) loncastuximab tesirine volume of distribution was 7.14 (22.9%) L.
SG3199 is a substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, OATP1B3, or organic cation transporter (OCT)1.
SG3199 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, OCT2, OCT1, multi-antimicrobial extrusion protein (MATE)1, MATE2-K, or bile salt export pump (BSEP) at clinically relevant unconjugated SG3199 concentrations.
The monoclonal antibody portion of loncastuximab tesirine is expected to be metabolised into small peptides by catabolic pathways. The small molecule cytotoxin, SG3199, is metabolised by CYP3A4/5 in vitro.
Cytochrome P450 (CYP) enzymes: SG3199 does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant unconjugated SG3199 concentrations.
The geometric mean (CV%) loncastuximab tesirine clearance decreased with time from 0.34 L/day (53.2%) after a single dose to 0.26 L/day (37.2%) at steady state. The mean (standard deviation) half-life of loncastuximab tesirine was 15.8 (6.26) days in Cycle 1 and 20.5 (5.72) days at steady state.
The major excretion pathways of SG3199 have not been studied in humans. Data collected in an animal model (rat) show minimal renal excretion. No clinical data are available.
No clinically significant differences in the pharmacokinetics of loncastuximab tesirine were observed based on age (20-94 years), sex, race (White vs. Black), body weight (42.1 to 160.5 kg), ECOG status (0 to 2) or mild to moderate renal impairment (CLcr 30 to <90 mL/min using the Cockcroft-Gault equation).
The clearance of loncastuximab tesirine in patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min using the Cockcroft-Gault equation) was not significantly different from patients with normal renal function.
For SG3199, data collected in an animal model (rat) show minimal renal excretion. No clinical data are available.
Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) may increase the exposure of unconjugated SG3199, however there was no clinically significant effect on loncastuximab tesirine pharmacokinetics.
Loncastuximab tesirine has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST).
Carcinogenicity studies have not been conducted with loncastuximab tesirine or SG3199.
SG3199 was genotoxic in an in vitro micronucleus test and a chromosome aberration assay using human lymphocytes through a clastogenic mechanism. These results are consistent with the pharmacological effect of SG3199 as a covalent DNA crosslinking agent. Results of a bacterial reverse mutation assay (Ames test) were inconclusive due to cytotoxicity.
No dedicated reproductive toxicity studies in animals have been conducted with loncastuximab tesirine.
However, the cytotoxic component of loncastuximab tesirine, SG3199, crosslinks DNA, is genotoxic, and is toxic to rapidly dividing cells, suggesting it has the potential to cause embryo-foetal toxicity.
Fertility studies have not been conducted with loncastuximab tesirine.
Results from repeat-dose toxicity studies with intravenous administration of loncastuximab tesirine in cynomolgus monkeys indicate the potential for impaired male reproductive function and fertility. Administration of loncastuximab tesirine to cynomolgus monkeys every 3 weeks at 0.6 mg/kg for a total of 2 doses, or every 3 weeks at 0.3 mg/kg for 13 weeks for a total of 5 doses resulted in adverse findings that included decreased weight and/or size of the testes and epididymis, atrophy of the seminiferous tubules, germ cell degeneration, and/or reduced epididymal sperm content. The dose of 0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at the maximum recommended human dose [MRHD] of 0.15 mg/kg. Findings were not reversible at the end of the 12-week recovery period following 4 or 13 weeks of dosing.
In repeat-dose toxicity studies in cynomolgus monkeys, intravenous administration of loncastuximab tesirine was associated with renal toxicity including increased kidney weights and nephropathy with variable reversible inflammation and fibrosis.
Black skin spots potentially related to phototoxicity were observed in cynomolgus monkeys and were still present after a 12-week treatment-free period.
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