Bispecific antibodies: a mechanistic review of the pipeline

Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

(2018) Nicola Gökbuget et al.   BLOOD

Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade

(2018) Cecile A.W. Geuijen et al.   CANCER CELL

IFN-γ-induced chemokines are required for CXCR3-mediated T cell recruitment and anti-tumor efficacy of anti-HER2/CD3 bispecific antibody

(2018) Ji Li et al.   CLINICAL CANCER RESEARCH

Therapeutic bispecific antibody formats: a patent applications review (1994-2017)

(2018) Marie Godar et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose

(2018) Aurelia H. M. de Vries Schultink et al.   INVESTIGATIONAL NEW DRUGS

Design and evaluation of bi- and trispecific antibodies targeting multiple filovirus glycoproteins

(2018) Elisabeth K. Nyakatura et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Antiviral Activity of HIV gp120-Targeting Bispecific T Cell Engager Antibody Constructs

(2018) Johannes Brozy et al.   JOURNAL OF VIROLOGY

ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models

(2018) Yingchun Li et al.   MOLECULAR CANCER THERAPEUTICS

Relative Target Affinities of T-Cell–Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model

(2018) Danielle Mandikian et al.   MOLECULAR CANCER THERAPEUTICS

Generation of orthogonal Fab-based trispecific antibody formats

(2018) Xiufeng Wu et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity

(2018) James J. Steinhardt et al.   Nature Communications

CD16A Activation of NK Cells Promotes NK Cell Proliferation and Memory-Like Cytotoxicity against Cancer Cells

(2018) Jens H.W. Pahl et al.   Cancer Immunology Research

Sequence-Based Discovery Demonstrates That Fixed Light Chain Human Transgenic Rats Produce a Diverse Repertoire of Antigen-Specific Antibodies

(2018) Katherine E. Harris et al.   Frontiers in Immunology

Tribody [(HER2)2xCD16] Is More Effective Than Trastuzumab in Enhancing γδ T Cell and Natural Killer Cell Cytotoxicity Against HER2-Expressing Cancer Cells

(2018) Hans H. Oberg et al.   Frontiers in Immunology

Endosome trafficking: blood and more

(2018) Gary M. Kupfer   BLOOD

A phase II study of ruxolitinib in combination with azacytidine in patients with myelofibrosis

(2018) Lucia Masarova et al.   BLOOD

Abstract 2784: Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation

(2018) Michael Hedvat et al.   CANCER RESEARCH

A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors

(2018) Antonio Jimeno et al.   INVESTIGATIONAL NEW DRUGS

EFab domain substitution as a solution to the light-chain pairing problem of bispecific antibodies

(2018) Heather A. Cooke et al.   mAbs

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

(2018) Sijia Huang et al.   mAbs

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors

(2018) Johnny Mahlangu et al.   NEW ENGLAND JOURNAL OF MEDICINE

Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair

(2018) Zhenhua Li et al.   ACS Nano

Bispecific antibodies: Potential immunotherapies for HIV treatment

(2018) Giulia Fabozzi et al.   METHODS

A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats

(2018) Gregory L. Moore et al.   METHODS

Engineering a bispecific antibody with a common light chain: Identification and optimization of an anti-CD3 epsilon and anti-GPC3 bispecific antibody, ERY974

(2018) Hirotake Shiraiwa et al.   METHODS

CD3-bispecific antibody therapy turns solid tumors into inflammatory sites but does not install protective memory

(2018) Hreinn Benonisson et al.   MOLECULAR CANCER THERAPEUTICS

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

(2018) Dionysos Slaga et al.   Science Translational Medicine

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity

(2018) Marta Compte et al.   Nature Communications

A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G 1

(2017) Camilla De Nardis et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice

(2017) Megan Lo et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies

(2017) Darko Skegro et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Direct demonstration of a neonatal Fc receptor (FcRn)-driven endosomal sorting pathway for cellular recycling of albumin

(2017) Esben G. W. Schmidt et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Bispecific antibody targets multiple Pseudomonas aeruginosa evasion mechanisms in the lung vasculature

(2017) Ajitha Thanabalasuriar et al.   JOURNAL OF CLINICAL INVESTIGATION

Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL

(2017) J Duell et al.   LEUKEMIA

A high-throughput platform for population reformatting and mammalian expression of phage display libraries to enable functional screening as full-length IgG

(2017) Xiaodong Xiao et al.   mAbs

Productive common light chain libraries yield diverse panels of high affinity bispecific antibodies

(2017) Thomas Van Blarcom et al.   mAbs

The making of bispecific antibodies

(2017) Ulrich Brinkmann et al.   mAbs

Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies

(2017) Elie Dheilly et al.   MOLECULAR THERAPY

Elimination of large tumors in mice by mRNA-encoded bispecific antibodies

(2017) Christiane R Stadler et al.   NATURE MEDICINE

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

(2017) Jedd D. Wolchok et al.   NEW ENGLAND JOURNAL OF MEDICINE

Emicizumab Prophylaxis in Hemophilia A with Inhibitors

(2017) Johannes Oldenburg et al.   NEW ENGLAND JOURNAL OF MEDICINE

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

(2017) Hagop Kantarjian et al.   NEW ENGLAND JOURNAL OF MEDICINE

Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells

(2017) Thorsten Gantke et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Novel CH1:CL interfaces that enhance correct light chain pairing in heterodimeric bispecific antibodies

(2017) Maximilian Bönisch et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

(2017) Ling Xu et al.   SCIENCE

An anti–glypican 3/CD3 bispecific T cell–redirecting antibody for treatment of solid tumors

(2017) Takahiro Ishiguro et al.   Science Translational Medicine

Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens

(2017) Keiko Esaki et al.   THROMBOSIS AND HAEMOSTASIS

Efficient Generation of Bispecific Murine Antibodies for Pre-Clinical Investigations in Syngeneic Rodent Models

(2017) Aran F. Labrijn et al.   Scientific Reports

Platelet-Targeted Delivery of Peripheral Blood Mononuclear Cells to the Ischemic Heart Restores Cardiac Function after Ischemia-Reperfusion Injury

(2017) Melanie Ziegler et al.   Theranostics

Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays

(2017) Marie Tosolini et al.   OncoImmunology

Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody

(2017) Andres Lopez-Albaitero et al.   OncoImmunology

In Situ Liver Expression of HBsAg/CD3-Bispecific Antibodies for HBV Immunotherapy

(2017) Robert L. Kruse et al.   Molecular Therapy-Methods & Clinical Development

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

(2016) D. Kavanagh et al.   BLOOD

Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking

(2016) Friederike Braig et al.   BLOOD

An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia

(2016) Steven R. Leong et al.   BLOOD

A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy

(2016) John Y. Li et al.   CANCER CELL

A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor–Resistant Lung Tumors

(2016) Sheri L. Moores et al.   CANCER RESEARCH

Characterization of CD33/CD3 Tetravalent Bispecific Tandem Diabodies (TandAbs) for the Treatment of Acute Myeloid Leukemia

(2016) U. Reusch et al.   CLINICAL CANCER RESEARCH

A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

(2016) M. Bacac et al.   CLINICAL CANCER RESEARCH

Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases

(2016) Jörg T Regula et al.   EMBO Molecular Medicine

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

(2016) Binyam Bezabeh et al.   mAbs

Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody

(2016) Songmao Zheng et al.   mAbs

An efficient route to bispecific antibody production using single-reactor mammalian co-culture

(2016) Whitney Shatz et al.   mAbs

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

(2016) Anke Steinmetz et al.   mAbs

Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells

(2016) Katharine D. Grugan et al.   mAbs

The use of CrossMAb technology for the generation of bi- and multispecific antibodies

(2016) Christian Klein et al.   mAbs

Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63

(2016) B. E. C. G. de Goeij et al.   MOLECULAR CANCER THERAPEUTICS

Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker

(2016) Joerg U Schmohl et al.   MOLECULAR THERAPY

Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A

(2016) Midori Shima et al.   NEW ENGLAND JOURNAL OF MEDICINE

TetraMabs: simultaneous targeting of four oncogenic receptor tyrosine kinases for tumor growth inhibition in heterogeneous tumor cell populations

(2016) Raffaella Castoldi et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions

(2016) Tilman Schlothauer et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Hitting Ebola, to the power of two

(2016) Aran F. Labrijn et al.   SCIENCE

A “Trojan horse” bispecific-antibody strategy for broad protection against ebolaviruses

(2016) Anna Z. Wec et al.   SCIENCE

Computationally Designed Bispecific Antibodies using Negative State Repertoires

(2016) Andrew Leaver-Fay et al.   STRUCTURE

Immune-mediated liver injury of the cancer therapeutic antibody catumaxomab targeting EpCAM, CD3 and Fcγ receptors

(2016) Jürgen Borlak et al.   Oncotarget

T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts

(2016) Judith Feucht et al.   Oncotarget

CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1

(2015) Takuya Osada et al.   CANCER IMMUNOLOGY IMMUNOTHERAPY

Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cells

(2015) Julia A.M. Sung et al.   JOURNAL OF CLINICAL INVESTIGATION

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study

(2015) Max S Topp et al.   LANCET ONCOLOGY

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

(2015) C Krupka et al.   LEUKEMIA

Improving target cell specificity using a novel monovalent bispecific IgG design

(2015) Yariv Mazor et al.   mAbs

Protein design of IgG/TCR chimeras for the co-expression of Fab-like moieties within bispecific antibodies

(2015) Xiufeng Wu et al.   mAbs

Alternative molecular formats and therapeutic applications for bispecific antibodies

(2015) Christoph Spiess et al.   MOLECULAR IMMUNOLOGY

Development of a Trispecific Antibody Designed to Simultaneously and Efficiently Target Three Different Antigens on Tumor Cells

(2015) Nazzareno Dimasi et al.   MOLECULAR PHARMACEUTICS

The prognostic landscape of genes and infiltrating immune cells across human cancers

(2015) Andrew J Gentles et al.   NATURE MEDICINE

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

(2015) Maarten Van Roy et al.   ARTHRITIS RESEARCH & THERAPY

Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG

(2015) Nicolas Fischer et al.   Nature Communications

Activation and lysis of human CD4 cells latently infected with HIV-1

(2015) Amarendra Pegu et al.   Nature Communications

Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex

(2015) Ganesh Kolumam et al.   EBioMedicine

Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

(2014) S. Hu et al.   CANCER RESEARCH

Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells

(2014) T. T. Junttila et al.   CANCER RESEARCH

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

(2014) Michael D Oberst et al.   mAbs

Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

(2014) James J. H. Chong et al.   NATURE

Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface

(2014) Steven M Lewis et al.   NATURE BIOTECHNOLOGY

Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle

(2014) Jens Niewoehner et al.   NEURON

Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates

(2014) Y. J. Yu et al.   Science Translational Medicine

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

(2014) A. DiGiandomenico et al.   Science Translational Medicine

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

(2013) G. S. Laszlo et al.   BLOOD

Drugs derived from phage display

(2013) Andrew E Nixon et al.   mAbs

Improving biophysical properties of a bispecific antibody scaffold to aid developability

(2013) Thomas Spreter Von Kreudenstein et al.   mAbs

Generation and characterization of monospecific and bispecific hexavalent trimerbodies

(2013) Ana Blanco-Toribio et al.   mAbs

Understanding the role of cross-arm binding efficiency in the activity of monoclonal and multispecific therapeutic antibodies

(2013) Brian D. Harms et al.   METHODS

An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations

(2013) Omid Vafa et al.   METHODS

A Heterodimeric Fc-Based Bispecific Antibody Simultaneously Targeting VEGFR-2 and Met Exhibits Potent Antitumor Activity

(2013) H.-J. Choi et al.   MOLECULAR CANCER THERAPEUTICS

Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies

(2013) Christoph Spiess et al.   NATURE BIOTECHNOLOGY

Identification and Multidimensional Optimization of an Asymmetric Bispecific IgG Antibody Mimicking the Function of Factor VIII Cofactor Activity

(2013) Zenjiro Sampei et al.   PLoS One

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange

(2013) A. F. Labrijn et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab

(2012) M. Klinger et al.   BLOOD

Natural IgM in Immune Equilibrium and Harnessing Their Therapeutic Potential

(2012) S. V. Kaveri et al.   JOURNAL OF IMMUNOLOGY

Generating Bispecific Human IgG1 and IgG2 Antibodies from Any Antibody Pair

(2012) Pavel Strop et al.   JOURNAL OF MOLECULAR BIOLOGY

A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens

(2012) Gregory L. Moore et al.   mAbs

Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site

(2012) Thomas List et al.   mAbs

Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens

(2012) M. Friedrich et al.   MOLECULAR CANCER THERAPEUTICS

Monoclonal TCR-redirected tumor cell killing

(2012) Nathaniel Liddy et al.   NATURE MEDICINE

A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model

(2012) Takehisa Kitazawa et al.   NATURE MEDICINE

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma

(2011) P. A. Moore et al.   BLOOD

Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies

(2011) W. Schaefer et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting

(2010) Markus Kügler et al.   BRITISH JOURNAL OF HAEMATOLOGY

Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen

(2010) Claudia Bluemel et al.   CANCER IMMUNOLOGY IMMUNOTHERAPY

The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial

(2010) Markus M. Heiss et al.   INTERNATIONAL JOURNAL OF CANCER

Development of a Two-part Strategy to Identify a Therapeutic Human Bispecific Antibody That Inhibits IgE Receptor Signaling

(2010) Janet Jackman et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Enhancing Antibody Fc Heterodimer Formation through Electrostatic Steering Effects

(2010) Kannan Gunasekaran et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Molecular construction and optimization of anti-human IL-1α/β dual variable domain immunoglobulin (DVD-IgTM) molecules

(2010) Chengbin Wu et al.   mAbs

Research Resource: Comprehensive Expression Atlas of the Fibroblast Growth Factor System in Adult Mouse

(2010) Klementina Fon Tacer et al.   MOLECULAR ENDOCRINOLOGY

T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells

(2010) Ralf Lutterbuese et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies†

(2010) Jonathan H. Davis et al.   PROTEIN ENGINEERING DESIGN & SELECTION

Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects

(2009) Jing Xu et al.   AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

Potent Control of Tumor Growth by CEA/CD3-bispecific Single-chain Antibody Constructs That Are Not Competitively Inhibited by Soluble CEA

(2009) Ralf Lutterbuese et al.   JOURNAL OF IMMUNOTHERAPY

Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

(2008) M. Amann et al.   CANCER RESEARCH

Fibroblast Growth Factor 21 Corrects Obesity in Mice

(2008) Tamer Coskun et al.   ENDOCRINOLOGY

Tumor Regression in Cancer Patients by Very Low Doses of a T Cell-Engaging Antibody

(2008) R. Bargou et al.   SCIENCE