Esther Breij - Academia.edu (original) (raw)

Papers by Esther Breij

Research paper thumbnail of Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism

Molecular Cancer Therapeutics

Research paper thumbnail of Abstract 4544: Multifaceted mechanism of action of DuoHexaBody-CD37 involves both complement- and Fc gamma receptor-mediated cytotoxicity in pre-clinical B-cell lymphoma models

Research paper thumbnail of DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies

Research paper thumbnail of Hexamerization-enhanced CD37 and CD20 antibodies synergize in CDC to kill patient-derived CLL cells with unprecedented potency

Research paper thumbnail of Use of an antibody-drug conjugate targeting tissue factor to induce complete tumor regression in xenograft models with heterogeneous target expression

Journal of Clinical Oncology

3066 Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circul... more 3066 Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. In addition, the TF:FVIIa complex can initiate a pro-angiogenic signaling pathway by activation of PAR-2. TF is aberrantly expressed in many solid tumors, and expression has been associated with poor prognosis. TF-011-vcMMAE, an antibody-drug conjugate (ADC) under development for the treatment of solid tumors, is composed of a human TF specific antibody (TF-011), a proteaseEcleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Methods: TF-011 and TF-011-vcMMAE were functionally characterized using in vitro assays. In vivo anti-tumor activity of TF-011-vcMMAE was assessed in human biopsy derived xenograft models, which genetically and histologically resemble human tumors. TF expression in xenografts was assessed using immunohistochemistry. Results: TF-011 inhibited TF:FVIIa induce...

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

Research paper thumbnail of Hexabody-CD38, a Novel CD38 Antibody with a Hexamerization Enhancing Mutation, Demonstrates Enhanced Complement-Dependent Cytotoxicity and Shows Potent Anti-Tumor Activity in Preclinical Models of Hematological Malignancies

Blood

HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superi... more HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superior complement dependent cytotoxicity (CDC) activity, in addition to other effector mechanisms. HexaBody-CD38 carries the E430G mutation and binds a different epitope than the clinically validated CD38 monoclonal antibody daratumumab, which is currently being established as backbone therapy for the treatment of multiple myeloma. Introduction of the E430G mutationfacilitates the natural process of antibody hexamer formation through increased intermolecular Fc-Fc interactions after antigen binding at the cell surface (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). Improved IgG hexamer formation can increase binding of the hexavalent complement component C1q, thereby potentiating or unlocking antibody-mediated complement-dependent cytotoxicity (CDC). Preclinical data demonstrate highly potent CDC-mediated tumor cell kill in vitro in a panel of cell lines derived from hemato...

Research paper thumbnail of Duobody-CD3xCD20 Induces Potent Anti-Tumor Activity in Malignant Lymph Node B Cells from Patients with DLBCL, FL and MCL Ex Vivo, Irrespective of Prior Treatment with CD20 Monoclonal Antibodies

Blood

DuoBody-CD3xCD20 (GEN3013) is a novel clinical-stage CD3 bispecific antibody (bsAb) targeting CD2... more DuoBody-CD3xCD20 (GEN3013) is a novel clinical-stage CD3 bispecific antibody (bsAb) targeting CD20-positive tumor cells. GEN3013 was previously shown to induce potent T cell-mediated cytotoxicity towards B cell Non-Hodgkin lymphoma (B-NHL) cell lines in vitro and in vivo. Here, we investigated the cytotoxic activity of GEN3013 in tumor cells obtained from lymph node (LN) biopsies of B-NHL patients, who were newly diagnosed (ND) or relapsed from/refractory to (RR) treatment regimens containing CD20 monoclonal antibodies. Moreover, we explored whether specific tumor microenvironment characteristics could be associated with sensitivity to GEN3013. To test the intrinsic susceptibility of B-NHL cells to GEN3013, independent of interpatient variation in tumor T cell frequency or activation status, single cell suspensions obtained from LN of B-NHL patients were incubated with GEN3013 in the presence of allogeneic PBMC from a single donor, at an effector to target (E:T) ratio 10:1. GEN3013 ...

Research paper thumbnail of Targeting CD37 in B-Cell Malignancies Using the Novel Therapeutic Duohexabody-CD37 Results in Efficient Killing of Tumor B-Cells Ex Vivo Via Complement-Dependent Cytotoxicity, Even in Relapsed and/or Refractory Patient Samples

Blood

CD37 is a tetraspanin molecule expressed on mature B-cells, but absent on normal stem cells and p... more CD37 is a tetraspanin molecule expressed on mature B-cells, but absent on normal stem cells and plasma cells. Due to this cellular distribution, which is highly similar to CD20, CD37 has gained attention as a target for B-cell lymphoma, especially for rituximab-resistant and relapsed patients. The CD37-targeting antibody-based products that are currently being evaluated in the clinic are generally poor inducers of complement-dependent cytotoxicity (CDC) - a rapid and powerful Fc-mediated effector function. DuoHexaBody-CD37 is a bispecific IgG1 antibody targeting two non-overlapping epitopes in the large extracellular loop of CD37, with a hexamerization-enhancing mutation (E430G) in the IgG Fc domain. The E430G mutation increases the intrinsic capacity of IgG1 molecules to form hexameric antibody clusters upon binding to membrane-bound antigens, thereby facilitating binding of the hexavalent complement component C1q and subsequent CDC activity (Diebolder et al., Science 2014; de Jong...

Research paper thumbnail of Duohexabody-CD37, a Novel Bispecific Antibody with a Hexamerization-Enhancing Mutation Targeting CD37, Demonstrates Superior Complement-Dependent Cytotoxicity in Preclinical B-Cell Malignancy Models

Blood

CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a pr... more CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a promising therapeutic target for the treatment of B-cell malignancies. Although complement-dependent cytotoxicity (CDC) has proven to be a powerful Fc-mediated effector function for killing hematological cancer cells, CD37 antibody-based therapeutics currently in clinical development are poor inducers of CDC. Here we present DuoHexaBody-CD37, a novel humanized IgG1 bispecific antibody targeting two different CD37 epitopes, with an E430G hexamerization-enhancing mutation, for the potential treatment of B-cell malignancies. The natural process of antibody hexamer formation through intermolecular Fc-Fc interactions between IgG molecules after cell surface antigen binding can be improved by introducing a single point mutation such as E430G in the IgG Fc domain, thereby facilitating more efficient C1q binding and complement activation (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2...

Research paper thumbnail of Duobody-CD3xCD20 Shows Unique and Potent Preclinical Anti-Tumor Activity in Vitro and In Vivo, and Is Being Evaluated Clinically in Patients with B-Cell Malignancies

Blood

DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 a... more DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 and the B-cell antigen CD20, that triggers potent T-cell-mediated lysis of CD20-expressing cells. DuoBody-CD3xCD20 is a full-length bispecific IgG1 generated by controlled Fab-arm exchange (cFAE) [1, 2] and contains an effector function-silenced Fc region. In vitro, DuoBody-CD3xCD20 induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells, as measured by flow cytometry and bromodeoxyuridine (BrdU) incorporation assays. DuoBody-CD3xCD20 induced T-cell-mediated cytotoxicity towards a diverse panel of cell lines derived from various B-cell malignancies and endogenous B cells, with EC50 values in the low picomolar range (EC50: 0.2-5.0 pM). The CD20-specific antibody 7D8 [3-5] forms the basis for the CD20-specific Fab arm of DuoBody-CD3xCD20. To study the contribution of this specific Fab arm to the observed potency ...

Research paper thumbnail of Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

Research paper thumbnail of Abstract 221: Tisotumab vedotin induces anti-tumor activity through MMAE-mediated, Fc-mediated, and Fab-mediated effector functionsin vitro

Experimental and Molecular Therapeutics

Research paper thumbnail of Abstract 2391: DR5 agonist activity of HexaBody®-DR5/DR5 (GEN1029) is potentiated by C1q and independent of Fc-gamma receptor binding in preclinical tumor models

Research paper thumbnail of Response to Comment on “Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells”

The Journal of Immunology

Research paper thumbnail of Abstract 832: An AXL-specific antibody-drug conjugate shows preclinical anti-tumor activity in non-small cell lung cancer, including EGFR-inhibitor resistant NSCLC

Experimental and Molecular Therapeutics

Research paper thumbnail of Preclinical efficacy studies using HuMax-Axl-ADC, a novel antibody-drug conjugate targeting Axl-expressing solid cancers

Journal of Clinical Oncology

Research paper thumbnail of CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering

Research paper thumbnail of Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Nature medicine, 2018

Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer l... more Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK...

Research paper thumbnail of Abstract 4591: Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL

Research paper thumbnail of Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism

Molecular Cancer Therapeutics

Research paper thumbnail of Abstract 4544: Multifaceted mechanism of action of DuoHexaBody-CD37 involves both complement- and Fc gamma receptor-mediated cytotoxicity in pre-clinical B-cell lymphoma models

Research paper thumbnail of DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies

Research paper thumbnail of Hexamerization-enhanced CD37 and CD20 antibodies synergize in CDC to kill patient-derived CLL cells with unprecedented potency

Research paper thumbnail of Use of an antibody-drug conjugate targeting tissue factor to induce complete tumor regression in xenograft models with heterogeneous target expression

Journal of Clinical Oncology

3066 Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circul... more 3066 Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. In addition, the TF:FVIIa complex can initiate a pro-angiogenic signaling pathway by activation of PAR-2. TF is aberrantly expressed in many solid tumors, and expression has been associated with poor prognosis. TF-011-vcMMAE, an antibody-drug conjugate (ADC) under development for the treatment of solid tumors, is composed of a human TF specific antibody (TF-011), a proteaseEcleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Methods: TF-011 and TF-011-vcMMAE were functionally characterized using in vitro assays. In vivo anti-tumor activity of TF-011-vcMMAE was assessed in human biopsy derived xenograft models, which genetically and histologically resemble human tumors. TF expression in xenografts was assessed using immunohistochemistry. Results: TF-011 inhibited TF:FVIIa induce...

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

Research paper thumbnail of Hexabody-CD38, a Novel CD38 Antibody with a Hexamerization Enhancing Mutation, Demonstrates Enhanced Complement-Dependent Cytotoxicity and Shows Potent Anti-Tumor Activity in Preclinical Models of Hematological Malignancies

Blood

HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superi... more HexaBody-CD38 (GEN3014) is a novel, hexamerization-enhanced human IgG1 targeting CD38 with superior complement dependent cytotoxicity (CDC) activity, in addition to other effector mechanisms. HexaBody-CD38 carries the E430G mutation and binds a different epitope than the clinically validated CD38 monoclonal antibody daratumumab, which is currently being established as backbone therapy for the treatment of multiple myeloma. Introduction of the E430G mutationfacilitates the natural process of antibody hexamer formation through increased intermolecular Fc-Fc interactions after antigen binding at the cell surface (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2016). Improved IgG hexamer formation can increase binding of the hexavalent complement component C1q, thereby potentiating or unlocking antibody-mediated complement-dependent cytotoxicity (CDC). Preclinical data demonstrate highly potent CDC-mediated tumor cell kill in vitro in a panel of cell lines derived from hemato...

Research paper thumbnail of Duobody-CD3xCD20 Induces Potent Anti-Tumor Activity in Malignant Lymph Node B Cells from Patients with DLBCL, FL and MCL Ex Vivo, Irrespective of Prior Treatment with CD20 Monoclonal Antibodies

Blood

DuoBody-CD3xCD20 (GEN3013) is a novel clinical-stage CD3 bispecific antibody (bsAb) targeting CD2... more DuoBody-CD3xCD20 (GEN3013) is a novel clinical-stage CD3 bispecific antibody (bsAb) targeting CD20-positive tumor cells. GEN3013 was previously shown to induce potent T cell-mediated cytotoxicity towards B cell Non-Hodgkin lymphoma (B-NHL) cell lines in vitro and in vivo. Here, we investigated the cytotoxic activity of GEN3013 in tumor cells obtained from lymph node (LN) biopsies of B-NHL patients, who were newly diagnosed (ND) or relapsed from/refractory to (RR) treatment regimens containing CD20 monoclonal antibodies. Moreover, we explored whether specific tumor microenvironment characteristics could be associated with sensitivity to GEN3013. To test the intrinsic susceptibility of B-NHL cells to GEN3013, independent of interpatient variation in tumor T cell frequency or activation status, single cell suspensions obtained from LN of B-NHL patients were incubated with GEN3013 in the presence of allogeneic PBMC from a single donor, at an effector to target (E:T) ratio 10:1. GEN3013 ...

Research paper thumbnail of Targeting CD37 in B-Cell Malignancies Using the Novel Therapeutic Duohexabody-CD37 Results in Efficient Killing of Tumor B-Cells Ex Vivo Via Complement-Dependent Cytotoxicity, Even in Relapsed and/or Refractory Patient Samples

Blood

CD37 is a tetraspanin molecule expressed on mature B-cells, but absent on normal stem cells and p... more CD37 is a tetraspanin molecule expressed on mature B-cells, but absent on normal stem cells and plasma cells. Due to this cellular distribution, which is highly similar to CD20, CD37 has gained attention as a target for B-cell lymphoma, especially for rituximab-resistant and relapsed patients. The CD37-targeting antibody-based products that are currently being evaluated in the clinic are generally poor inducers of complement-dependent cytotoxicity (CDC) - a rapid and powerful Fc-mediated effector function. DuoHexaBody-CD37 is a bispecific IgG1 antibody targeting two non-overlapping epitopes in the large extracellular loop of CD37, with a hexamerization-enhancing mutation (E430G) in the IgG Fc domain. The E430G mutation increases the intrinsic capacity of IgG1 molecules to form hexameric antibody clusters upon binding to membrane-bound antigens, thereby facilitating binding of the hexavalent complement component C1q and subsequent CDC activity (Diebolder et al., Science 2014; de Jong...

Research paper thumbnail of Duohexabody-CD37, a Novel Bispecific Antibody with a Hexamerization-Enhancing Mutation Targeting CD37, Demonstrates Superior Complement-Dependent Cytotoxicity in Preclinical B-Cell Malignancy Models

Blood

CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a pr... more CD37 is a tetraspanin plasma membrane protein abundantly expressed on B-cells and represents a promising therapeutic target for the treatment of B-cell malignancies. Although complement-dependent cytotoxicity (CDC) has proven to be a powerful Fc-mediated effector function for killing hematological cancer cells, CD37 antibody-based therapeutics currently in clinical development are poor inducers of CDC. Here we present DuoHexaBody-CD37, a novel humanized IgG1 bispecific antibody targeting two different CD37 epitopes, with an E430G hexamerization-enhancing mutation, for the potential treatment of B-cell malignancies. The natural process of antibody hexamer formation through intermolecular Fc-Fc interactions between IgG molecules after cell surface antigen binding can be improved by introducing a single point mutation such as E430G in the IgG Fc domain, thereby facilitating more efficient C1q binding and complement activation (Diebolder et al., Science 2014; de Jong et al., PLoS Biol 2...

Research paper thumbnail of Duobody-CD3xCD20 Shows Unique and Potent Preclinical Anti-Tumor Activity in Vitro and In Vivo, and Is Being Evaluated Clinically in Patients with B-Cell Malignancies

Blood

DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 a... more DuoBody®-CD3xCD20 (GEN3013) is a bispecific antibody (bsAb), recognizing the T-cell antigen CD3 and the B-cell antigen CD20, that triggers potent T-cell-mediated lysis of CD20-expressing cells. DuoBody-CD3xCD20 is a full-length bispecific IgG1 generated by controlled Fab-arm exchange (cFAE) [1, 2] and contains an effector function-silenced Fc region. In vitro, DuoBody-CD3xCD20 induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells, as measured by flow cytometry and bromodeoxyuridine (BrdU) incorporation assays. DuoBody-CD3xCD20 induced T-cell-mediated cytotoxicity towards a diverse panel of cell lines derived from various B-cell malignancies and endogenous B cells, with EC50 values in the low picomolar range (EC50: 0.2-5.0 pM). The CD20-specific antibody 7D8 [3-5] forms the basis for the CD20-specific Fab arm of DuoBody-CD3xCD20. To study the contribution of this specific Fab arm to the observed potency ...

Research paper thumbnail of Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

Research paper thumbnail of Abstract 221: Tisotumab vedotin induces anti-tumor activity through MMAE-mediated, Fc-mediated, and Fab-mediated effector functionsin vitro

Experimental and Molecular Therapeutics

Research paper thumbnail of Abstract 2391: DR5 agonist activity of HexaBody®-DR5/DR5 (GEN1029) is potentiated by C1q and independent of Fc-gamma receptor binding in preclinical tumor models

Research paper thumbnail of Response to Comment on “Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells”

The Journal of Immunology

Research paper thumbnail of Abstract 832: An AXL-specific antibody-drug conjugate shows preclinical anti-tumor activity in non-small cell lung cancer, including EGFR-inhibitor resistant NSCLC

Experimental and Molecular Therapeutics

Research paper thumbnail of Preclinical efficacy studies using HuMax-Axl-ADC, a novel antibody-drug conjugate targeting Axl-expressing solid cancers

Journal of Clinical Oncology

Research paper thumbnail of CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering

Research paper thumbnail of Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Nature medicine, 2018

Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer l... more Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK...

Research paper thumbnail of Abstract 4591: Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL