Journal Articles

Antibody-based therapy

Therapies based on monoclonal antibodies, antibody derivatives, antibody-drug conjugates, bispecific antibodies, immunotoxins, etc. (except for immune checkpoint therapies)

Blocking "don't eat me" signal of CD47-SIRPalpha in hematological malignancies, an in-depth review

More

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPalpha triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPalpha resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPalpha interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPalpha interaction in leukemia, lymphoma and multiple myeloma.

Author Info: (1) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: aruss@deptofmed.arizona.edu. (2) Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA. Electronic address

Author Info: (1) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: aruss@deptofmed.arizona.edu. (2) Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA. Electronic address: anhhua@email.arizona.edu. (3) Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA. Electronic address: montfort@email.arizona.edu. (4) Department of Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: bushra.rahman@bannerhealth.com. (5) Department of Medicine, Hematology Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: riaz.dr@mayo.edu. (6) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: umarkhalid1990@gmail.com. (7) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: jcarew@email.arizona.edu. (8) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: snawrocki@email.arizona.edu. (9) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: dpersky@email.arizona.edu. (10) Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address: anwerf@email.arizona.edu.

Less

CD20-TCB with obinutuzumab pretreatment as next generation treatment of hematological malignancies

More

PURPOSE: Despite promising clinical activity, T cell engaging therapies including T cell bispecific antibodies (TCBs) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug. EXPERIMENTAL DESIGN: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity pre-clinically. We also applied a single administration of obinutuzumab (Gazyva pre-treatment, Gpt) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug. RESULTS: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B and T cell binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B cell depletion in peripheral blood and secondary lymphoid organs and reduces T cell activation and cytokine release in the peripheral blood thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD. CONCLUSIONS: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in Phase I, multicenter study in patients with relapsed/refractory NHL (NCT03075696).

Author Info: (1) Oncology DTA, Roche Innovation Center Zurich marina.bacac@roche.com. (2) Pharmacology, Roche Innovation Center Zurich. (3) Pharma Research and Early Development, Roche Innovation Center Zurich. (4)

Author Info: (1) Oncology DTA, Roche Innovation Center Zurich marina.bacac@roche.com. (2) Pharmacology, Roche Innovation Center Zurich. (3) Pharma Research and Early Development, Roche Innovation Center Zurich. (4) Oncology DTA, Roche Innovation Center Zurich, Roche Pharmaceutical Research & Early Development, pRED. (5) Oncology Discovery Pharmacology, pRED, Roche Innovation Center Zurich. (6) Roche Innovation Center Zurich. (7) Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development. (8) CIT-2, Roche Innovation Center Zurich. (9) Roche Innovation Center Zurich. (10) Pharmaceutical Research and Early Development, Roche Innovation Center Zurich. (11) Roche Innovation Center Zurich. (12) Pharmaceutical Sciences, Roche Innovation Center Basel. (13) Pharmaceutical Sciences, Roche Innovation Center Basel. (14) Immunopathology, Roche Innovation Center Zurich. (15) PS, Pathology, Roche Innovation Center Zurich. (16) Large Molecule Research, Roche Pharmaceutical Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, CH-8952 Schlieren. (17) Large Molecule Research, Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED). (18) Large Molecule Research, Roche Innovation Center Zurich. (19) ROCHE Pharma Research and Early Development: Discovery Oncology, ROCHE Innovation Center Zurich. (20) Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich.

Less

Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia

More

The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in >90% of ALL patients, and inotuzumab ozogamicin has shown excellent clinical activity even among heavily pretreated relapsed/refractory (R/R) B-ALL patients and elderly B-ALL patients. Clinical trials have shown superior survival with the drug over chemotherapy-based approaches in the first- or second-line salvage therapy for relapsed B-ALL as monotherapy. Currently, new trials are evaluating inotuzumab ozogamicin in the frontline setting in combination-based approaches. In this review, we summarize the preclinical and clinical data of inotuzumab ozogamicin in R/R B-ALL and foresee the future use of this drug in the clinic.

Author Info: (1) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (2) Section of Hematology, Department of Internal Medicine, Yale

Author Info: (1) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (2) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (3) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (4) Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Less

Internalization of CD239 highly expressed in breast cancer cells: a potential antigen for antibody-drug conjugates

More

Antibody-drug conjugates (ADCs) are attractive in cancer therapy because they can directly bind to cancer cells and provide anticancer activity. To kill cancer cells with ADCs, the target antigens are required not only to be highly and/or selectively expressed on cancer cells but also internalized by the cells. CD239, also known as the Lutheran blood group glycoprotein (Lu) or basal cell adhesion molecule (B-CAM), is a specific receptor for laminin alpha5, a major component of basement membranes. Here, we show that CD239 is strongly expressed in a subset of breast cancer cells and internalized into the cells. We also produced a human single-chain variable fragment (scFv) specific to CD239 fused with human IgG1 Fc, called C7-Fc. The binding affinity of the C7-Fc antibody is similar to that of mouse monoclonal antibodies. Although the C7-Fc antibody alone does not influence cellular functions, when conjugated with a fragment of diphtheria toxin lacking the receptor-binding domain (fDT), it can selectively kill breast cancer cells. Interestingly, fDT-bound C7-Fc shows anticancer activity in CD239-highly positive SKBR3 cells, but not in weakly positive cells. Our results show that CD239 is a promising antigen for ADC-based breast cancer therapy.

Author Info: (1) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. kikkawa@toyaku.ac.jp. (2) Graduate School of Science and Engineering, Kagoshima University

Author Info: (1) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. kikkawa@toyaku.ac.jp. (2) Graduate School of Science and Engineering, Kagoshima University, Kagoshima, 890-0065, Japan. (3) Graduate School of Science and Engineering, Kagoshima University, Kagoshima, 890-0065, Japan. (4) Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. Department of Neurology, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, 113-8421, Japan. (5) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (6) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (7) Department of Drug Delivery and Molecular Biopharmaceutics, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (8) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (9) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (10) Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392, Japan. (11) Graduate School of Science and Engineering, Kagoshima University, Kagoshima, 890-0065, Japan.

Less

Chimeric Small Antibody Fragments as Strategy to Deliver Therapeutic Payloads

More

Antibody-drug conjugates (ADCs) represent an innovative class of biopharmaceuticals, which aim at achieving a site-specific delivery of cytotoxic agents to the target cell. The use of ADCs represents a promising strategy to overcome the disadvantages of conventional pharmacotherapy of cancer or neurological diseases, based on cytotoxic or immunomodulatory agents. ADCs consist of monoclonal antibodies attached to biologically active drugs by means of cleavable chemical linkers. Advances in technologies for the coupling of antibodies to cytotoxic drugs promise to deliver greater control of drug pharmacokinetic properties and to significantly improve pharmacodelivery applications, minimizing exposure of healthy tissue. The clinical success of brentuximab vedotin and trastuzumab emtansine has led to an extensive expansion of the clinical ADC pipeline. Although the concept of an ADC seems simple, designing a successful ADC is complex and requires careful selection of the receptor antigen, antibody, linker, and payload. In this review, we explore insights in the antibody and antigen requirements needed for optimal payload delivery and support the development of novel and improved ADCs for the treatment of cancer and neurological diseases.

Author Info: (1) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (2) Centro de

Author Info: (1) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (2) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (3) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (4) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (5) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. (6) Centro de Investigacao Interdisciplinar em Sanidade Animal (CIISA), Faculdade de Medicina Veterinaria, Universidade de Lisboa, Avenida da Universidade Tecnica, Lisboa, Portugal. (7) iMed.ULisboa-Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. Electronic address: joao.goncalves@ff.ul.pt.

Less

Developing Anti-HER2 Vaccines: Breast Cancer Experience

More

Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumour proliferation rates. Trastuzumab-based therapies are effectively and widely used as standard of care in HER2-amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody-dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen-specific immunotherapy to trigger the patient's immune system to target HER2-overexpressing tumour cells, which led to the development of various vaccines against the HER2 antigen. This manuscript discusses the various anti-HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings. This article is protected by copyright. All rights reserved.

Author Info: (1) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Breast Medical Oncology, The University of

Author Info: (1) Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Less

Bevacizumab Reduces S100A9(+) MDSC Linked to Intracranial Control in Patients with EGFR Mutant Lung Adenocarcinoma

More

BACKGROUND: In vitro models have demonstrated immune-modulating effects of bevacizumab. Combinations of EGFR tyrosine kinase inhibitor (TKI) with bevacizumab improve progression free survival (PFS) in patients with EGFR mutated lung adenocarcinoma. How bevacizumab confers this clinical effect and underlying mechanisms are not clear. PATIENT AND METHODS: Fifty-five patients with stage 4 EGFR mutated lung adenocarcinoma were enrolled. Myeloid derived suppressor cells (MDSCs), T helper cells (Th1/Th2) and cytotoxic T lymphocytes (CTLs) were analyzed by flow cytometry. Clinical data were collected for analysis. RESULT: Twenty-five patients received EGFR-TKI and BEV combination therapy (BEV/TKI group) and thirty patients received EGFR-TKI (TKI group) monotherapy. BEV/TKI group had longer PFS (23.0 vs. 8.6 months, p=0.001) and, particularly, better intracranial control rates (80.0% vs. 43.0%, p=0.03), longer time to intracranial progression (49.1 vs. 12.9 months, p=0.002) and fewer new brain metastases (38.0% vs. 71.0%, p=0.03) than TKI group. BEV/TKI group had lower circulating MDSCs (20.4+/-6.5% vs. 12.8+/-6.6%, pre- vs. post-treatment, respectively, p=0.02) and higher Th1 (22.9+/-15.3% vs. 33.2+/-15.6%, p<0.01) and CTLs (15.5+/-7.2% vs. 21.2+/-5.6%, p<0.01) after treatment, changes which were not seen in the TKI only group. Pretreatment MDSC was correlated with PFS, which correlation was attenuated after Bev/TKI treatment. MDSC was also associated with shorter time to intracranial progression. CONCLUSION: Combining EGFR-TKI with bevacizumab extended PFS and protected from brain metastasis. Those effects were probably due to bevacizumab reduction of circulating S100A9(+) MDSCs, leading to restoration of effective anti-tumor immunity. Our data also support the rationale for BEV-immune checkpoint inhibitors combination.

Author Info: (1) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Pulmomary Medicine, Department of Internal Medicine

Author Info: (1) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Pulmomary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. (2) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. (3) Division of Pulmonary Medicine, Department of Internal Medicine, Chang Gung Medical Foundation, Linko Branch, Taoyuan, Taiwan. (4) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (5) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (6) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (7) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (8) Department of Medical Research and Education, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (9) School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. (10) Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei Taiwan. (11) Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. (12) Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan. (13) Division of Pulmonary Medicine, Department of Internal Medicine, Chang Gung Medical Foundation, Linko Branch, Taoyuan, Taiwan. Electronic address: lee4949@ms41.hinet.net. (14) Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Division of Pulmomary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: lee4949@ms41.hinet.net.

Less

Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer

More

Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a pro-tumor phenotype. Correlation to clinical data only showed a weak trend towards worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1 and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (2) Department of Microbiology

Author Info: (1) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (2) Department of Microbiology, Tumor and Cell biology, Karolinska institutet, Stockholm, Sweden. (3) Department of Microbiology, Tumor and Cell biology, Karolinska institutet, Stockholm, Sweden. National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Solna, Sweden. (4) Epistat, Uppsala, Sweden. (5) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (6) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (7) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (8) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (9) Division of Pathology, Lund University, Skane University Hospital, Lund, Sweden. (10) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. Department of Respiratory Medicine, Gavle Hospital, Gavle, Sweden. Centre for Research and Development, Uppsala University, County Council of Gavleborg, Sweden. (11) Department of Respiratory Medicine, Gavle Hospital, Gavle, Sweden. Centre for Research and Development, Uppsala University, County Council of Gavleborg, Sweden. (12) Department of Respiratory Medicine, Gavle Hospital, Gavle, Sweden. Centre for Research and Development, Uppsala University, County Council of Gavleborg, Sweden. (13) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden. (14) Department of Microbiology, Tumor and Cell biology, Karolinska institutet, Stockholm, Sweden. (15) Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.

Less

Activity of Indatuximab Ravtansine against Triple-Negative Breast Cancer in Preclinical Tumor Models

More

PURPOSE: Triple-negative breast cancer (TNBC) is related with a poor prognosis as patients do hardly benefit from approved therapies. CD138 (Syndecan-1) is upregulated on human breast cancers. Indatuximab ravtansine (BT062) is an antibody-drug-conjugate that specifically targets CD138-expressing cells and has previously shown clinical activity in multiple myeloma. Here we show indatuximab ravtansine as a potential mono- and combination therapy for TNBC. METHODS: The effects of indatuximab ravtansine were assessed in vitro in SK-BR-3 and T47D breast cancer cell lines. The in vivo effects of indatuximab ravtansine alone and in combination with docetaxel or paclitaxel were assessed in MAXF401, MAXF1384 and MAXF1322 xenograft TNBC models. RESULTS: CD138(+) SK-BR-3 and T47D cells were highly sensitive to indatuximab ravtansine. The high CD138-expressing MAXF401 xenograft model demonstrated strong inhibition of tumor growth with 4 mg/kg indatuximab ravtansine. High doses of indatuximab ravtansine (8 mg/kg), docetaxel and the combination of both led to complete remission. In the low CD138-expressing MAXF1384 xenograft model, only combination of indatuximab ravtansine and docetaxel demonstrated a significant efficacy. In the MAXF1322 xenograft model, indatuximab ravtansine alone and in combination with paclitaxel elicited complete remission. CONCLUSIONS: These data demonstrate potential use of indatuximab ravtansine in combination with docetaxel or paclitaxel for CD138-positive TNBC.

Author Info: (1) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (2) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (3)

Author Info: (1) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (2) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (3) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (4) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (5) Corporate Project & Portfolio Management, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (6) Corporate Project & Portfolio Management, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. (7) Corporate Research & Development, Biotest AG, Landsteinerstrasse 5, 63303, Dreieich, Germany. joerg.schuettrumpf@biotest.com.

Less

A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells

More

The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease. Here we describe the development and preclinical characterization of a CD123-targeting antibody-drug conjugate (ADC), IMGN632, that comprises a novel humanized anti-CD123 antibody G4723A linked to a recently reported DNA mono-alkylating payload of the indolinobenzodiazepine pseudodimer (IGN) class of cytotoxic compounds. The activity of IMGN632 was compared with X-ADC, the ADC utilizing the G4723A antibody linked to a DNA crosslinking IGN payload. With low picomolar potency, both ADCs reduced viability in AML cell lines and patient-derived samples in culture, irrespective of their multidrug resistance or disease status. However, X-ADC exposure was >40-fold more cytotoxic to the normal myeloid progenitors than IMGN632. Of particular note, IMGN632 demonstrated potent activity in all AML samples at concentrations well below levels that impacted normal bone marrow progenitors, suggesting the potential for efficacy in AML patients in the absence of or with limited myelosuppression. Furthermore, IMGN632 demonstrated robust antitumor efficacy in multiple AML xenograft models. Overall, these findings identify IMGN632 as a promising candidate for evaluation as a novel therapy in AML.

Author Info: (1) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (2) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (3) Science, Technology, and Translation, ImmunoGen, Inc

Author Info: (1) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (2) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (3) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (4) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (5) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (6) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (7) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (8) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (9) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (10) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (11) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (12) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (13) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (14) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (15) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (16) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA. (17) Science, Technology, and Translation, ImmunoGen, Inc, Waltham MA.

Less