The Role of FcRn in the Pharmacokinetics of Biologics in Patients With Multiple Myeloma

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To the Editor: Daratumumab is the first monoclonal antibody (mAb) approved for patients with multiple myeloma (MM). Understanding daratumumab pharmacokinetics (PK) is crucial to reach a safe dosing schedule with optimal efficacy. Xu et al. describe the PK of intravenous daratumumab, a human IgG mAb exerting its therapeutic effect through binding to CD38 that is expressed on myeloma cells.1 In their article they investigate factors affecting daratumumab PK.
The authors observed nonlinear PK in which increasing dose and repeated dosing led to decreased daratumumab clearance.1 This was attributed to target‐mediated clearance, whereby the anti‐CD38 target becomes saturated and reduced over time due to tumor burden reduction. We hypothesize that the saturation of the neonatal Fc‐receptor (FcRn) plays an important additional role in the nonlinear PK characteristics of biologics in this unique patient cohort.
Following uptake of plasma proteins by endothelial cells, IgG antibodies are recycled by FcRn, protecting them from catabolism, thus prolonging half‐life (Figure1a).2 Morell et al. showed that elevated IgG substantially shortened half‐life for all subclasses of IgG.3 More than 50% of the MM patients have an IgG M‐protein.4 A vast majority of these patients present with an M‐protein concentration of more than 30 g/L, and often exceeds 50 g/L.4 These IgG concentrations saturate FcRn, resulting in shortened half‐life of all IgG subclasses.5 We hypothesize that in this situation, exogenously administered IgG biologics will also exhibit a shortened half‐life.
The PK of daratumumab administered in the presence or absence of high IgG M‐protein concentrations is illustrated via simulation (Figure1b). Daratumumab trough levels will be up to 50% lower in a patient with 60 g/L IgG M‐protein (green line) compared to a patient with 60 g/L IgA M‐protein (red line). In order to maintain similar daratumumab trough levels in both patients, we estimate that the daratumumab dose should be increased from 16 mg/kg to 30 mg/kg in a patient with 60 g/L IgG M‐protein.
If the patient responds well to therapy, and IgG M‐protein decreases, FcRn will be no longer saturated and daratumumab PK will resemble that of a patient with an IgA M‐protein. Measurement of M‐protein concentration in these patients may therefore contribute both to assessing therapeutic response and optimizing daratumumab dosing.
Shortened half‐life of biologics in MM patients with high IgG M‐proteins will likely apply to the rapidly expanding list of other emerging IgG biologics for the treatment of MM.

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