Tafasitamab is an Fc-enhanced monoclonal antibody that targets the CD19 antigen expressed on the surface of pre-B and mature B lymphocytes.
Upon binding to CD19, tafasitamab mediates B-cell lysis through:
The Fc modification results in enhanced antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.
In patients with relapsed or refractory DLBCL, tafasitamab led to a reduction in peripheral blood B-cell counts. The reduction relative to baseline B-cell count reached 97% after eight days of treatment in the L-MIND study. The maximum B-cell reduction at approximately 100% (median) was reached within 16 weeks of treatment.
Although the depletion of B-cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B-cells in solid organs or in malignant deposits.
The absorption, distribution, biotransformation and elimination were documented based on a population pharmacokinetic analysis.
Based on an analysis of tafasitamab in combination with lenalidomide, tafasitamab average serum trough concentrations (± standard deviation) were 179 (± 53) μg/mL during weekly (plus an additional dose on day 4 of cycle 1) intravenous administrations of 12 mg/kg. During administration every 14 days from cycle 4 onwards, average trough serum concentrations were 153 (± 68) μg/mL. Overall maximum tafasitamab serum concentrations were 483 (± 109) μg/mL.
The total volume of distribution for tafasitamab was 9.3 L.
The exact pathway through which tafasitamab is metabolised has not been characterised. As a human IgG monoclonal antibody, tafasitamab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The clearance of tafasitamab was 0.41 L/day and terminal elimination half-life was 16.9 days. Following long-term observations, tafasitamab clearance was found to decrease over time to 0.19 L/day after two years.
Age, body weight, sex, tumour size, disease type, B-cell or absolute lymphocyte counts, anti-drug antibodies, lactate dehydrogenase and serum albumin levels had no relevant effect on the pharmacokinetics of tafasitamab. The influence of race and ethnicity on the pharmacokinetics of tafasitamab is unknown.
The effect of renal impairment was not formally tested in dedicated clinical trials; however, no clinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mild to moderate renal impairment (creatinine clearance (CrCL) ≥30 and <90 mL/min estimated by the Cockcroft-Gault equation). The effect of severe renal impairment to end-stage renal disease (CrCL <30 mL/min) is unknown.
The effect of hepatic impairment was not formally tested in dedicated clinical trials; however no clinically meaningful differences in the pharmacokinetics of tafasitamab were observed for mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin 1 to 1.5 times ULN and any AST). The effect of moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST) is unknown.
Preclinical data reveal no special hazards for humans.
Tafasitamab has shown to be highly specific to the CD19 antigen on B cells. Toxicity studies following intravenous administration to cynomolgus monkeys have shown no other effect than the expected pharmacological depletion of B-cells in peripheral blood and in lymphoid tissues. These changes reversed after cessation of treatment.
As tafasitamab is a monoclonal antibody, genotoxicity and carcinogenicity studies have not been conducted, since such tests are not relevant for this molecule in the proposed indication.
Reproductive and developmental toxicity studies as well as specific studies to evaluate the effects on fertility have not been conducted with tafasitamab. However, no adverse effects on reproductive organs in males and females and no effects on menstrual cycle length in females were observed in the 13-week repeat-dose toxicity study in cynomolgus monkeys.
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