Glofitamab (RO7082859) is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Glofitamab leads to T-cell activation, proliferation, and tumor cell killing upon binding to CD20 on malignant cells. Glofitamab induces durable complete remissions in relapsed or refractory B-Cell non-Hodgkin lymphoma (B-NHL) [1] [2] [3] [4].
In Vivo, Glofitamab (0.3-100 μg/kg, i.v., a single dose) induces a dose-dependent increase in cytokine levels (IL-1Ra, IL-2, IL-5, IL-6, IL-8, IL-10, G-CSF, IFN-γ and TNF-α) in Cynomolgus Monkeys[3]. Glofitamab (0.5 mg/kg, i.v., a single dose) induces early and lasting T cell engagement and activity in mice[5]. Pharmacokinetic parameters of Glofitamab (i.v., a single dose) in cynomolgus monkeys with or without Obinutuzumab (Gpt: 50 mg/kg) (MeSt: Mechanistic Study; MTD: Maximum Tolerated Dose)[3] Study Gpt Dose (μg/kg) CL(mL/day/kg) Vc(mL/kg) T1/2 (days) Cmax (μg/mL) AUClast/dose(h·μg/mL/μg/kg) MTD No 0.3 nd nd nd 0.00374/0.00663 nd MTD No 1 nd 45.6/nd nd 0.0188/nd 0.0162/nd MTD No 3 864/920 35.8/31.9 0.218/0.180 0.0704/0.0798 0.0218/0.0234 MTD No 10 735/656 26.7/24.6 0.143/0.159 0.318/0.354 0.0290/0.0339 MTD No 30 600/653 27.9/36.1 0.173/0.151 0.958/0.759 0.0397/0.0335 MTD No 100 190/290 34.9/41.6 0.203/0.113 2.74/2.29 0.126/0.0826 MeSt No 100 384±106 43.2±7.26 0.314±0.158 2.22±0.384 0.0679±0.0246 MeSt Yes 100 81.7±18.3 41.1±5.59 2.82±0.959 2.56±0.320 0.308±0.0773
In Vitro, Glofitamab (0.1 µg/mL, 48 h) stimulates the expression of 4-1BB (CD137) on CD8+ tumor-infiltrating lymphocyte (TILs) in the lymphoma tumor microenvironment (TMEs) and augmented diffuse large B cell lymphoma (DLBCL) cell death combined with either FAP-IL2v or FAP-4-1BBL[4]. Glofitamab (0.2-200 ng/mL, 16 h)-mediated DLBCL cell killing requires the formation of stable T effector cell-tumor cell synapses[5]. Glofitamab has no effect on the transient reduction in T-lymphocyte subsets, NK cells and monocytes by Obinutuzumab pretreatment (Gpt)[3].
References:
[1]. Hutchings M, et al. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021;39(18):1959-1970.
[2]. Bröske AE, et al. Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. Blood Adv. 2022;6(3):1025-1037.
[3]. Frances N, et al. Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab. J Pharm Sci. 2022 Apr;111(4):1208-1218.
[4]. Apollonio B, et al. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma. J Clin Invest. 2023 Jul 3;133(13):e166070.
[5]. Cremasco F, et al. Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model. PLoS One. 2021 Jan 6;16(1):e0241091.
In Vivo, Glofitamab (0.3-100 μg/kg, i.v., a single dose) induces a dose-dependent increase in cytokine levels (IL-1Ra, IL-2, IL-5, IL-6, IL-8, IL-10, G-CSF, IFN-γ and TNF-α) in Cynomolgus Monkeys[3]. Glofitamab (0.5 mg/kg, i.v., a single dose) induces early and lasting T cell engagement and activity in mice[5]. Pharmacokinetic parameters of Glofitamab (i.v., a single dose) in cynomolgus monkeys with or without Obinutuzumab (Gpt: 50 mg/kg) (MeSt: Mechanistic Study; MTD: Maximum Tolerated Dose)[3] Study Gpt Dose (μg/kg) CL(mL/day/kg) Vc(mL/kg) T1/2 (days) Cmax (μg/mL) AUClast/dose(h·μg/mL/μg/kg) MTD No 0.3 nd nd nd 0.00374/0.00663 nd MTD No 1 nd 45.6/nd nd 0.0188/nd 0.0162/nd MTD No 3 864/920 35.8/31.9 0.218/0.180 0.0704/0.0798 0.0218/0.0234 MTD No 10 735/656 26.7/24.6 0.143/0.159 0.318/0.354 0.0290/0.0339 MTD No 30 600/653 27.9/36.1 0.173/0.151 0.958/0.759 0.0397/0.0335 MTD No 100 190/290 34.9/41.6 0.203/0.113 2.74/2.29 0.126/0.0826 MeSt No 100 384±106 43.2±7.26 0.314±0.158 2.22±0.384 0.0679±0.0246 MeSt Yes 100 81.7±18.3 41.1±5.59 2.82±0.959 2.56±0.320 0.308±0.0773
In Vitro, Glofitamab (0.1 µg/mL, 48 h) stimulates the expression of 4-1BB (CD137) on CD8+ tumor-infiltrating lymphocyte (TILs) in the lymphoma tumor microenvironment (TMEs) and augmented diffuse large B cell lymphoma (DLBCL) cell death combined with either FAP-IL2v or FAP-4-1BBL[4]. Glofitamab (0.2-200 ng/mL, 16 h)-mediated DLBCL cell killing requires the formation of stable T effector cell-tumor cell synapses[5]. Glofitamab has no effect on the transient reduction in T-lymphocyte subsets, NK cells and monocytes by Obinutuzumab pretreatment (Gpt)[3].
References:
[1]. Hutchings M, et al. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021;39(18):1959-1970.
[2]. Bröske AE, et al. Pharmacodynamics and molecular correlates of response to glofitamab in relapsed/refractory non-Hodgkin lymphoma. Blood Adv. 2022;6(3):1025-1037.
[3]. Frances N, et al. Novel in Vivo and in Vitro Pharmacokinetic/Pharmacodynamic-Based Human Starting Dose Selection for Glofitamab. J Pharm Sci. 2022 Apr;111(4):1208-1218.
[4]. Apollonio B, et al. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma. J Clin Invest. 2023 Jul 3;133(13):e166070.
[5]. Cremasco F, et al. Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model. PLoS One. 2021 Jan 6;16(1):e0241091.