A Dose Escalation Study of RO7082859 as a Single Agent and in Combination With Obinutuzumab, Administered After a Fixed, Single Pre-Treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma
A Study of RO7082859 in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Participants With Non-Hodgkin Lymphomas and Participants With DLBCL
This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.
CD20- and CD3-targeting bispecific antibody for B-cell malignancies
Glofitamab (also known as RO7082859, RG6026) is an investigational, full-length, CD20- and CD3-targeting T-cell bispecific antibody that is designed to redirect T cells to engage and eliminate malignant B cells.1-4 Glofitamab is designed to bind to CD20, a B-cell surface protein expressed in a majority of B-cell malignancies, while simultaneously binding to CD3, a component of the TCR on the surface of T cells.1,2,5,6 Glofitamab is equipped with an Fc region that has been engineered to abolish FcγRs and C1q binding while maintaining FcRn binding, which may allow for an extended circulatory half-life.1,2,7 In preclinical models, glofitamab demonstrated anticancer activity, including T-cell activation, proliferation, and B-cell killing.1,2 Furthermore, glofitamab administered with a PD-L1– blocking antibody led to enhanced inhibition of tumor growth in preclinical combination studies.2
1. Optimized structure facilitates activity against cancer cells
Glofitamab is an investigational, T-cell bispecific antibody with a distinctive design that features 2 Fab arms for binding CD20 on B cells, along with 1 Fab arm for binding CD3 on T cells. The CD3 binding arm is fused directly to one of the CD20-binding arms in a head-to-tail fashion via a short flexible linker. This unique structure allows for high-avidity binding to CD20 that can result in activity against B cells even under low effector-to-target (E:T) cell ratios.1,2
2. Developed to direct immune cells to attack and kill cancer cells
Upon binding to CD20 on a B cell and CD3 on a T cell, glofitamab may induce activation of the T cell and subsequent formation of an immunologic synapse between the two cells.1,2,6 This is followed by secretion of cytotoxic granules, including perforin and granzyme, by the activated T cell. Perforin creates large transmembrane pores on the surface of the bound B cell, allowing granzymes to enter the cell. Granzymes trigger a series of biochemical reactions, resulting in B-cell lysis.8,9
3. Anticancer effects demonstrated in preclinical studies
In preclinical models of multiple B-cell malignancies, glofitamab administration led to B-cell killing and tumor regression. Preclinical models also suggest glofitamab activity leads to the proliferation/expansion of T cells at the site of activation and increased intra-tumor T-cell infiltration.1,2 Glofitamab continues to be investigated in ongoing clinical trials, including in combination with PD-L1 inhibition, for B-cell malignancies.10
C1q=complement component 1, q subcomponent; CD=cluster of differentiation; Fab=fragment antigen binding; Fc=fragment crystallizable; FcγR=Fc gamma receptor; FcRn=neonatal Fc receptor; PD-L1=programmed death-ligand 1; TCR=T-cell receptor.
- Bacac M, Colombetti S, Herter S, et al. Clin Cancer Res. 2018. doi:10.1158/1078-0432.CCR-18-0455. PMID: 29716920
- Bacac M, Umaña P, Herter S, et al. Blood. 2016;128:1836.
- Joosten V, Lokman C, van den Hondel CA, Punt PJ. Microb Cell Fact. 2003;2:1. PMID: 12605725
- Johnson M. Labome validated antibody database. https://www.labome.com/method/Antibody-Structure-and-Fragments.html. Updated July 29, 2018. Accessed August 23, 2018.
- Prevodnik VK, Lavrenčak J, Horvat M, Novakovič BJ. Diagn Pathol. 2011;6:33. PMID: 21486448
- Frankel SR, Baeuerle PA. Curr Opin Chem Biol. 2013;17:385-392. PMID: 23623807
- Wang X, Mathieu M, Brezski RJ. Protein Cell. 2018;9:63-73. PMID: 28986820
- Dieckmann NMG, Frazer GL, Asano Y, Stinchcombe JC, Griffiths GM. J Cell Sci. 2016;129:2881-2886. PMID: 27505426
- Thiery J, Keefe D, Boulant S, et al. Nat Immunol. 2011;12:770-777. PMID: 21685908
- Roche first-quarter results 2020 presentation, https://www.roche.com/dam/jcr:f5b0e8e3-66fb-4155-85ff-ec1b012fb46c/en/irp200422.pdf. Accessed April 24, 2020.