DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing

Engelberts, Patrick J.; Hiemstra, Ida H.; Jong, Bart de; Schuurhuis, Danita H.; Meesters, Joyce; Hernández, Irati Beltrán; Oostindie, Simone C.; Neijssen, Joost; Brink, Edward N. van den; Horbach, G. Jean; Verploegen, Sandra; Labrijn, Aran F.; Salcedo, Theodora W.; Schuurman, Janine; Parren, Paul W.H.I.; Breij, Esther C.W.

doi:10.1016/j.ebiom.2019.102625

Cited by 94 publications

(112 citation statements)

References 45 publications

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“…There is a situation that the two targets are expressed by a tumor cell and an immune cell, respectively. In this case, CD3-based bispecific antibodies are most common, such as CD3xCD19 [63], CD3xCD20 [64], CD3xBCMA [65], CD3-HAC [66]. Because of the expression of CD3 in T cells, if the structural format is IgG-like, then IgG1 must not be selected.…”

Section: Selection Of Igg Subclasses For Bsabs Respectively Against Omentioning

confidence: 99%

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

2020

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The intact antibody of human immunoglobulin (IgG) is composed of the fragment for antigen binding (Fab) and the crystallizable fragment (Fc) for binding of Fcγ receptors. Among the four subclasses of human IgG (IgG1, IgG2, IgG3, IgG4), which differ in their constant regions, particularly in their hinges and CH2 domains, IgG1 has the highest FcγRbinding affinity, followed by IgG3, IgG2, and IgG4. As a result, different subclasses have different effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Fcγ receptors include six subtypes (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB) which differ in cellular distribution, binding affinity to Fc, and the resulting biological activity. Therefore, when developing anti-tumor therapeutic antibodies, including single-targeted antibodies, bi-specific antibodies (BsAbs), and antibody-drug conjugates (ADCs), many factors, such as target biology, cellular distribution of the targets, the environments of particular tumor types, as well as the proposed mechanism of action (MOA), must be taken into consideration. This review outlines fundamental strategies that are required to select IgG subclasses in developing anti-tumor therapeutic antibodies.

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Section: Selection Of Igg Subclasses For Bsabs Respectively Against Omentioning

confidence: 99%

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

2020

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“…Hence, major efforts are devoted to developing efficient chimeric antigen receptors (CARs) and T-cell engagers targeting CD20 5 – 11 . Epcoritamab (DuoBody®-CD3xCD20, GEN3013) is a novel full-length IgG1 bispecific antibody (bsAb) redirecting CD3 + T-cells to CD20 expressing cells 7 , 12 , 13 . In an initial study, we have shown that epcoritamab induces potent T-cell-mediated cytotoxicity towards B-cell NHL cell lines in vitro and in vivo 7 .…”

Section: Introductionmentioning

confidence: 99%

Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment

et al. 2021

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Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20+ tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.

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“…Responses were evaluated over a broad range of dosages with dosagedependent responses seen. With treatment ≥ 80 mg, the GEN3013, a CD20/CD3 BiTe, is an IgG1 antibody that is unique in that it is administered subcutaneously rather than IV [100]. In pre-clinical models, subcutaneous administration demonstrated similar bioavailability and B cell depletion as IV administration, but with lower plasma cytokine levels and was hypothesized to result in less CRS but with the same responses in patients [100].…”

Section: Bite Antibodiesmentioning

confidence: 99%

“…With treatment ≥ 80 mg, the GEN3013, a CD20/CD3 BiTe, is an IgG1 antibody that is unique in that it is administered subcutaneously rather than IV [100]. In pre-clinical models, subcutaneous administration demonstrated similar bioavailability and B cell depletion as IV administration, but with lower plasma cytokine levels and was hypothesized to result in less CRS but with the same responses in patients [100]. The preliminary results of a dose-escalation study on 18 patients with relapsed/refractory NHL (n = 14 with DLBCL), were presented at the 2019 ASH conference [99].…”

Section: Bite Antibodiesmentioning

confidence: 99%

Emerging therapies in mantle cell lymphoma

Hanel

Epperla

2020

J Hematol Oncol

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Mantle cell lymphoma (MCL) is a rare, B cell non-Hodgkin's lymphoma with highly heterogeneous clinical presentation and aggressiveness. First-line treatment consists of intensive chemotherapy with autologous stem cell transplant for the fit, transplant eligible patients, or less intensive chemotherapy for the less fit (and transplantineligible) patients. Patients eventually relapse with a progressive clinical course. Numerous therapeutic approaches have emerged over the last few years which have significantly changed the treatment landscape of MCL. These therapies consist of targeted approaches such as BTK and BCL2 inhibitors that provide durable therapeutic responses. However, the optimum combination and sequencing of these therapies is unclear and is currently investigated in several ongoing studies. Furthermore, cellular therapies such as chimeric antigen receptor (CAR) T cells and bispecific T cell engager (BiTe) antibodies have shown impressive results and will likely shape treatment approaches in relapsed MCL, especially after failure with BTK inhibitors. Herein, we provide a comprehensive review of past and ongoing studies that will likely significantly impact our approach to MCL treatment in both the frontline (for transplant eligible and ineligible patients) as well as in the relapsed setting. We present the most up to date results from these studies as well as perspectives on future studies in MCL.

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DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing

Cited by 94 publications

References 45 publications

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment

Emerging therapies in mantle cell lymphoma

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