Genentech Oncology
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.
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
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
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
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.
Watch how Glofitamab redirects T cells and how it engages B cells.
Watch how glofitamab redirects T cells and how it engages B cells.
Bacac M, Colombetti S, Herter S, et al. Clin Cancer Res. 2018. doi:10.1158/1078-0432.CCR-18-0455. PMID: 29716920
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.
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
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.
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
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
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
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
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
Thiery J, Keefe D, Boulant S, et al. Nat Immunol. 2011;12:770-777. PMID: 21685908
Roche. 2021 results. February 3, 2022. Accessed February 15, 2022. https://assets.cwp.roche.com/f/126832/x/baa445a513/irp220203-a.pdf
Roche. 2021 results. February 3, 2022. Accessed February 15, 2022. https://assets.cwp.roche.com/f/126832/x/baa445a513/irp220203-a.pdf
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