Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies

Abstract

Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first-in-human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half-maximal effective concentration values from in vitro cytokine release assays (range: 0.05-0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1-10 mg/L) were useful to predict efficacious concentrations in patients and inform dose-escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.

Conflict of interest statement

Min Zhu, Kara Olson, Jessica R. Kirshner, Masood Khaksar Toroghi, Hong Yan, Lauric Haber, Craig Meagher, Dina M. Flink, Srikanth R. Ambati, John D. Davis, A. Thomas DiCioccio, Eric J. Smith, and Marc W. Retter are employees and shareholders of Regeneron Pharmaceuticals, Inc.

© 2022 Regeneron Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Odronextamab‐induced cytokine release in human whole blood samples from multiple donors: EC50 (a) and maximum cytokine release (b). Data points represent individual donors. Box‐and‐whisker plots represent the median (central line), 25/75 percentiles (box), and min/max range (whiskers). Reported LLODs per Meso Scale Diagnostics documentation for Human ProInflammatory 4‐Plex Ultra‐Sensitive Kit: IFN‐γ, 0.40 pg/ml; IL‐6, 0.22 pg/ml; TNF‐α, 0.49 pg/ml. EC50, half‐maximal effective concentration; IFNγ, interferon‐γ; IL‐6, interleukin 6; LLOD, lower limit of detection; TNF‐α, tumor necrosis factor‐α

FIGURE 2

Odronextamab‐induced in vitro cytokine release is reduced in the presence of dexamethasone. In vitro cytokine profiles in (a) human whole blood samples from a healthy donor incubated with odronextamab or control antibody and (b) a 96‐h co‐culture assay with Raji and human PBMCs in the presence or absence of dexamethasone 300 nM. EC50 values for cytokine release were determined using GraphPad PrismTM software, with values calculated using a four‐parameter nonlinear regression analysis. Panel 1a shows representative data from one of 9–10 independent donors evaluated in single wells per condition. In Panel 1b, Raji +/− Dex was performed a single time; cytokines were evaluated from one assay well per condition. Ab, antibody; Dex, dexamethasone; EC50, half‐maximal effective concentration; IFN‐γ, interferon‐γ; IL‐6, interleukin 6; PBMCs, peripheral blood mononuclear cells; TNF‐α, tumor necrosis factor‐α

FIGURE 3

In vitro cytotoxicity of odronextamab against various CD20‐expressing lymphoma cell lines (a–d), and Raji cells in the presence of dexamethasone (e). Each plot shows representative results from independent experiments (Panel 2a: n = 11 experiments; 2b: n = 7 experiments; 2c: n = 5 experiments; 2d: n = 4 experiments; and 2e: n = 1 experiment). EC50 values were determined using GraphPad PrismTM software, with values calculated using a four‐parameter non‐linear regression analysis. Panels 2a, 2c, 2d, and 2e were performed in duplicate, with average values and standard deviations plotted; Panel 2b was performed in a single well per condition. Ab, antibody; Dex, dexamethasone; EC50, half‐maximal effective concentration

FIGURE 4

Odronextamab exposure (a) and antitumor effects (b) in immunocompromised nonobese diabetic (NOD) severe combined immunodeficiency (scid) γ mice bearing Raji cell xenografts. In NSG mice bearing Raji tumors co‐implanted with human PBMCs, single‐dose odronextamab (0.04, 0.1, 0.4, and 1.0 mg/kg) was administered intraperitoneally on day 0 when average tumor volume reached 220 mm3. Tumor volume in each treatment group was measured twice weekly and averages (mm3 ± SEM) are plotted. Grouped two‐way ANOVA (day 21) was performed using GraphPad PrismTM software. In Panel 3a, the gray dashed line represents a reference concentration of 1 µg/ml, at which a complete inhibition of tumor growth was achieved. In Panel 3b, asterisks indicate statistically significant differences in average tumor volume on day 21 compared with vehicle control group (***p ≤ 0.001; ****p ≤ 0.0001). ANOVA, analysis of variance; LLOQ, lower limit of quantification; NSG, NOD‐scid IL2Rgammanull; PBMCs, peripheral blood mononuclear cells; SEM, standard error of the mean

FIGURE 5

Mean concentration–time profiles for odronextamab at various dosesa (a) and relationship between mean odronextamab Cmax and mean peak IL‐6 level on day 1 following i.v. infusionb (b) in cynomolgus monkeys. aConcentration versus time profiles were imputed to ½ LLOQ. bIL‐6 production at 5 h following i.v. administration of odronextamab 0.01, 0.1, and 1 mg/kg. Cmax, maximum concentration; IL‐6, interleukin 6; i.v., intravenous; LLOQ, lower limit of quantification

FIGURE 6

Individual IL‐6 peak concentration versus odronextamab Cmax in week 1 (a) and week 2 (b) of treatment in patients with B‐cell non‐Hodgkin lymphoma. Note: Odronextamab serum concentration data taken from the dose‐escalation portion of the FIH clinical study R1979‐HM‐1333 (NCT02290951).n = number of patients in each dose group; color represents different dose group. Cmax, maximum concentration; FIH, first‐in‐human; IL‐6, interleukin 6