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Article ; Online: Preclinical evidence for the effective use of TL-895, a highly selective and potent second-generation BTK inhibitor, for the treatment of B-cell malignancies.

Goodstal, Samantha M / Lin, Jing / Crandall, Timothy / Crowley, Lindsey / Bender, Andrew T / Pereira, Albertina / Soloviev, Maria / Wesolowski, John S / Iadevaia, Riham / Schelhorn, Sven-Eric / Ross, Edith / Morandi, Federica / Ma, Jianguo / Clark, Anderson

Scientific reports

2023 Volume 13, Issue 1, Page(s) 20412

Abstract: TL-895 (formerly known as M7583) is a potent, highly selective, adenosine triphosphate (ATP)-competitive, second-generation, irreversible inhibitor of Bruton's tyrosine kinase (BTK). We characterized its biochemical and cellular effects in in vitro and ... ...

Abstract	TL-895 (formerly known as M7583) is a potent, highly selective, adenosine triphosphate (ATP)-competitive, second-generation, irreversible inhibitor of Bruton's tyrosine kinase (BTK). We characterized its biochemical and cellular effects in in vitro and in vivo models. TL-895 was evaluated preclinically for potency against BTK using IC
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; B-Lymphocytes/metabolism ; Agammaglobulinaemia Tyrosine Kinase ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Kinase Inhibitors/chemistry ; Lymphoma, Large B-Cell, Diffuse/pathology
Chemical Substances	Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-11-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-47735-z
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Article ; Online: M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

Xu, Chunxiao / Zhou, Xueyuan / Webb, Lindsay / Yalavarthi, Sireesha / Zheng, Wenxin / Saha, Somdutta / Schweickhardt, Rene / Soloviev, Maria / Jenkins, Molly H / Brandstetter, Susanne / Belousova, Natalya / Alimzhanov, Marat / Rabinovich, Brian / Deshpande, Amit M / Brewis, Neil / Helming, Laura

Cancer immunology research

2023 Volume 12, Issue 2, Page(s) 195–213

Abstract: The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist ... ...

Abstract	The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.
MeSH term(s)	Humans ; Animals ; Mice ; Mesothelin ; Neoplasms ; Chemical and Drug Induced Liver Injury ; Inflammation ; Tumor Necrosis Factor Receptor Superfamily, Member 9 ; Tumor Microenvironment
Chemical Substances	Mesothelin (J27WDC343N) ; Tumor Necrosis Factor Receptor Superfamily, Member 9
Language	English
Publishing date	2023-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0243
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Article ; Online: Coating a stainless steel plate with silver nanoparticles by the sonochemical method.

Soloviev, Maria / Gedanken, Aharon

Ultrasonics sonochemistry

2011 Volume 18, Issue 1, Page(s) 356–362

Abstract: Ultrasound irradiation is used for the deposition of silver nanoparticles with an average size of 40 nm on the surface of a stainless steel plate. The sonochemical reduction of an AgNO(3) solution (water, ethylene glycol and aqueous ammonia) was carried ... ...

Abstract	Ultrasound irradiation is used for the deposition of silver nanoparticles with an average size of 40 nm on the surface of a stainless steel plate. The sonochemical reduction of an AgNO(3) solution (water, ethylene glycol and aqueous ammonia) was carried out at 30°C. Irradiation was done with a high intensity ultrasonic horn (Ti horn from Sonics and Materials VCX600, 20 kHz, 600 W at 70% efficiency) under an argon flow. The influence of the distance of the stainless steel plate from the sonicator tip varied, and a homogeneous coating without agglomeration was achieved at a distance of 1 cm. By controlling the reaction conditions and the distance from the tip we could achieve a homogeneous monolayer coating of silver nanoparticles on the stainless steel surface. The silver-deposited stainless steel plates were analysed by UV-visible, XRD, SEM and FIB analyses.
MeSH term(s)	Metal Nanoparticles/chemistry ; Particle Size ; Silver/chemistry ; Stainless Steel/chemistry ; Surface Properties ; Ultrasonics
Chemical Substances	Stainless Steel (12597-68-1) ; Silver (3M4G523W1G)
Language	English
Publishing date	2011-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1208333-1
ISSN	1873-2828 ; 1350-4177
ISSN (online)	1873-2828
ISSN	1350-4177
DOI	10.1016/j.ultsonch.2010.06.015
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Article ; Online: Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses.

Lan, Yan / Yeung, Tsz-Lun / Huang, Hui / Wegener, Ansgar A / Saha, Somdutta / Toister-Achituv, Mira / Jenkins, Molly H / Chiu, Li-Ya / Lazorchak, Adam / Tarcic, Ohad / Wang, Hong / Qi, Jin / Locke, George / Kalimi, Doron / Qin, Guozhong / Marelli, Bo / Yu, Huakui / Gross, Alec W / Derner, Melissa G /

Soloviev, Maria / Botte, Mathieu / Sircar, Aroop / Ma, Hong / Sood, Vanita D / Zhang, Dong / Jiang, Feng / Lo, Kin-Ming

Journal for immunotherapy of cancer

2022 Volume 10, Issue 7

Abstract: Background: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor ... ...

Abstract	Background: Bintrafusp alfa (BA) is a bifunctional fusion protein designed for colocalized, simultaneous inhibition of two immunosuppressive pathways, transforming growth factor-β (TGF-β) and programmed death-ligand 1 (PD-L1), within the tumor microenvironment (TME). We hypothesized that targeting PD-L1 to the tumor by BA colocalizes the TGF-β trap (TGF-βRII) to the TME, enabling it to sequester TGF-β in the tumor more effectively than systemic TGF-β blockade, thereby enhancing antitumor activity. Methods: Multiple technologies were used to characterize the TGF-β trap binding avidity. BA versus combinations of anti-PD-L1 and TGF-β trap or the pan-TGF-β antibody fresolimumab were compared in proliferation and two-way mixed lymphocyte reaction assays. Immunophenotyping of tumor-infiltrating lymphocytes (TILs) and RNA sequencing (RNAseq) analysis assessing stromal and immune landscape following BA or the combination therapy were performed in MC38 tumors. TGF-β and PD-L1 co-expression and their associated gene signatures in MC38 tumors and human lung carcinoma tissue were studied with single-cell RNAseq (scRNAseq) and immunostaining. BA-induced internalization, degradation, and depletion of TGF-β were investigated in vitro. Results: BA and fresolimumab had comparable intrinsic binding to TGF-β1, but there was an ~80× avidity-based increase in binding affinity with BA. BA inhibited cell proliferation in TGF-β-dependent and PD-L1-expressing cells more potently than TGF-β trap or fresolimumab. Compared with the combination of anti-PD-L1 and TGF-β trap or fresolimumab, BA enhanced T cell activation in vitro and increased TILs in MC38 tumors, which correlated with efficacy. BA induced distinct gene expression in the TME compared with the combination therapy, including upregulation of immune-related gene signatures and reduced activities in TGF-β-regulated pathways, such as epithelial-mesenchymal transition, extracellular matrix deposition, and fibrosis. Regulatory T cells, macrophages, immune cells of myeloid lineage, and fibroblasts were key PD-L1/TGF-β1 co-expressing cells in the TME. scRNAseq analysis suggested BA modulation of the macrophage phenotype, which was confirmed by histological assessment. PD-L1/TGF-β1 co-expression was also seen in human tumors. Finally, BA induced TGF-β1 internalization and degradation in the lysosomes. Conclusion: BA more effectively blocks TGF-β by targeting TGF-β trap to the tumor via PD-L1 binding. Such colocalized targeting elicits distinct and superior antitumor responses relative to single agent combination therapy.
MeSH term(s)	B7-H1 Antigen ; Humans ; Immunologic Factors ; Lung Neoplasms ; Programmed Cell Death 1 Receptor ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1 ; Tumor Microenvironment
Chemical Substances	B7-H1 Antigen ; CD274 protein, human ; Immunologic Factors ; Programmed Cell Death 1 Receptor ; Transforming Growth Factor beta ; Transforming Growth Factor beta1
Language	English
Publishing date	2022-07-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-004122
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Article ; Online: Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule.

Kelton, Christie / Wesolowski, John S / Soloviev, Maria / Schweickhardt, Rene / Fischer, David / Kurosawa, Emmi / McKenna, Sean D / Gross, Alec W

Archives of biochemistry and biophysics

2012 Volume 526, Issue 2, Page(s) 219–225

Abstract: Certain combinations of non-competitive anti-EGFR antibodies have been reported to produce new effects on cells compared to either antibody used separately. New and enhanced combination-activity includes increased inhibition of signaling, increased ... ...

Abstract	Certain combinations of non-competitive anti-EGFR antibodies have been reported to produce new effects on cells compared to either antibody used separately. New and enhanced combination-activity includes increased inhibition of signaling, increased receptor internalization and degradation, reduced proliferation of tumor cell lines and induction of complement-dependent cytotoxicity (CDC) effector function. To test requirements and mechanisms to elicit enhanced combination-activity with different EGFR binding domains, we created an anti-EGFR biparatopic antibody. A biparatopic antibody interacts through two different antigen-binding sites to a single antigen. A heterodimeric antibody with one binding domain derived from the C225 antibody and one binding domain derived from the humanized 425 (hu425) antibody was built on the strand-exchange engineered domain (SEED) scaffold. This anti-EGFR biparatopic-SEED antibody was compared to parental antibodies used alone and in combination, and to the corresponding monovalent anti-EGFR-SEED antibodies used alone or in combination. We found that the anti-EGFR biparatopic-SEED had enhanced activity, similar to the combination of the two parental antibodies. Combinations of monovalent anti-EGFR-SEED antibodies did not produce enhanced effectiveness in cellular assays. Our results show that the anti-EGFR biparatopic antibody created using the SEED scaffold has enhanced combination-activity in a single molecule. Furthermore, these data suggest that the potential to cross-link the two different epitopes is an important requirement in the mechanism of enhanced combination-activity.
MeSH term(s)	Antibodies, Bispecific/chemistry ; Antibodies, Bispecific/immunology ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/immunology ; Binding Sites, Antibody ; Cell Line, Tumor ; Cell Proliferation ; Cetuximab ; Epitopes/immunology ; ErbB Receptors/immunology ; Humans ; Protein Structure, Tertiary
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Epitopes ; ErbB Receptors (EC 2.7.10.1) ; matuzumab (MG4M3QB242) ; Cetuximab (PQX0D8J21J)
Language	English
Publishing date	2012-03-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2012.03.005
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Article ; Online: Therapeutic assessment of SEED: a new engineered antibody platform designed to generate mono- and bispecific antibodies.

Muda, Marco / Gross, Alec W / Dawson, Jessica P / He, Chaomei / Kurosawa, Emmi / Schweickhardt, Rene / Dugas, Melanie / Soloviev, Maria / Bernhardt, Anna / Fischer, David / Wesolowski, John S / Kelton, Christie / Neuteboom, Berend / Hock, Bjoern

Protein engineering, design & selection : PEDS

2011 Volume 24, Issue 5, Page(s) 447–454

Abstract: The strand-exchange engineered domain (SEED) platform was designed to generate asymmetric and bispecific antibody-like molecules, a capability that expands therapeutic applications of natural antibodies. This new protein engineered platform is based on ... ...

Abstract	The strand-exchange engineered domain (SEED) platform was designed to generate asymmetric and bispecific antibody-like molecules, a capability that expands therapeutic applications of natural antibodies. This new protein engineered platform is based on exchanging structurally related sequences of immunoglobulin within the conserved CH3 domains. Alternating sequences from human IgA and IgG in the SEED CH3 domains generate two asymmetric but complementary domains, designated AG and GA. The SEED design allows efficient generation of AG/GA heterodimers, while disfavoring homodimerization of AG and GA SEED CH3 domains. Using a clinically validated antibody (C225), we tested whether Fab derivatives constructed on the SEED platform retain desirable therapeutic antibody features such as in vitro and in vivo stability, favorable pharmacokinetics, ligand binding and effector functions including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In addition, we tested SEED with combinations of binder domains (scFv, VHH, Fab). Mono- and bivalent Fab-SEED fusions retain full binding affinity, have excellent biochemical and biophysical stability, and retain desirable antibody-like characteristics conferred by Fc domains. Furthermore, SEED is compatible with different combinations of Fab, scFv and VHH domains. Our assessment shows that the new SEED platform expands therapeutic applications of natural antibodies by generating heterodimeric Fc-analog proteins.
MeSH term(s)	Animals ; Antibodies, Bispecific/chemistry ; Antibodies, Bispecific/genetics ; Antibodies, Bispecific/immunology ; Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Antibody Affinity ; Antibody Specificity ; Cell Line, Tumor ; Complement System Proteins/immunology ; Half-Life ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fab Fragments/genetics ; Immunoglobulin Fab Fragments/immunology ; Immunoglobulin G/genetics ; Male ; Mice ; Protein Engineering/methods ; Protein Multimerization ; Protein Stability ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/immunology
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal ; Immunoglobulin Fab Fragments ; Immunoglobulin G ; Complement System Proteins (9007-36-7) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Journal Article
ZDB-ID	1466729-0
ISSN	1741-0134 ; 1460-213X ; 1741-0126 ; 0269-2139
ISSN (online)	1741-0134 ; 1460-213X
ISSN	1741-0126 ; 0269-2139
DOI	10.1093/protein/gzq123
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Article: Mpp4 is required for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals.

Yang, Jun / Pawlyk, Basil / Wen, Xiao-Hong / Adamian, Michael / Soloviev, Maria / Michaud, Norman / Zhao, Yun / Sandberg, Michael A / Makino, Clint L / Li, Tiansen

Human molecular genetics

2007 Volume 16, Issue 9, Page(s) 1017–1029

Abstract: Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) ...

Abstract	Membrane palmitoylated protein 4 (Mpp4) is a member of the membrane-associated guanylate kinase family. We show that Mpp4 localizes specifically to the plasma membrane of photoreceptor synaptic terminals. Plasma membrane Ca(2+) ATPases (PMCAs), the Ca(2+) extrusion pumps, interact with an Mpp4-dependent presynaptic membrane protein complex that includes Veli3 and PSD95. In mice lacking Mpp4, PMCAs were lost from rod photoreceptor presynaptic membranes. Synaptic ribbons were enlarged, a phenomenon known to correlate with higher Ca(2+). SERCA2 (sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase, type 2), which pumps cytosolic Ca(2+) into intracellular Ca(2+) stores and localizes next to the ribbons, was increased. The distribution of IP(3)RII (InsP(3) receptor, type 2), which releases Ca(2+) from the stores, was shifted away from the synaptic terminals. Synaptic transmission to second-order neurons was maintained but was reduced in amplitude. These data suggest that loss of Mpp4 disrupts a Ca(2+) extrusion mechanism at the presynaptic membranes, with ensuing adaptive responses by the photoreceptor to restore Ca(2+) homeostasis. We propose that Mpp4 organizes a presynaptic protein complex that includes PMCAs and has a role in modulating Ca(2+) homeostasis and synaptic transmission in rod photoreceptors.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Calcium/metabolism ; Disks Large Homolog 4 Protein ; Fluorescent Antibody Technique ; Gene Deletion ; Guanylate Kinases ; Homeostasis ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Membrane Proteins/physiology ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Microscopy, Electron, Transmission ; Microscopy, Immunoelectron ; Models, Biological ; Multiprotein Complexes/metabolism ; Plasma Membrane Calcium-Transporting ATPases/genetics ; Plasma Membrane Calcium-Transporting ATPases/metabolism ; Presynaptic Terminals/metabolism ; Presynaptic Terminals/ultrastructure ; Protein Binding ; Retinal Rod Photoreceptor Cells/metabolism ; Retinal Rod Photoreceptor Cells/ultrastructure ; Synaptic Transmission/genetics ; Synaptic Transmission/physiology ; Two-Hybrid System Techniques
Chemical Substances	Adaptor Proteins, Signal Transducing ; Disks Large Homolog 4 Protein ; Dlg4 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Lin7c protein, mouse ; Membrane Proteins ; Mpp4 protein, mouse ; Multiprotein Complexes ; Guanylate Kinases (EC 2.7.4.8) ; Plasma Membrane Calcium-Transporting ATPases (EC 3.6.3.8) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2007-05-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddm047
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Article: Effects of low AIPL1 expression on phototransduction in rods.

Makino, Clint L / Wen, Xiao-Hong / Michaud, Norman / Peshenko, Igor V / Pawlyk, Basil / Brush, Richard S / Soloviev, Maria / Liu, Xiaoqing / Woodruff, Michael L / Calvert, Peter D / Savchenko, Andrey B / Anderson, Robert E / Fain, Gordon L / Li, Tiansen / Sandberg, Michael A / Dizhoor, Alexander M

Investigative ophthalmology & visual science

2006 Volume 47, Issue 5, Page(s) 2185–2194

Abstract: Purpose: To investigate the impact of aryl hydrocarbon receptor-interacting protein-like (AIPL)-1 on photoreception in rods.: Methods: Photoresponses of mouse rods expressing lowered amounts of AIPL1 were studied by single-cell and electroretinogram ( ...

Abstract	Purpose: To investigate the impact of aryl hydrocarbon receptor-interacting protein-like (AIPL)-1 on photoreception in rods. Methods: Photoresponses of mouse rods expressing lowered amounts of AIPL1 were studied by single-cell and electroretinogram (ERG) recordings. Phototransduction protein levels and enzymatic activities were determined in biochemical assays. Ca2+ dynamics were probed with a fluorescent dye. Comparisons were made to rods expressing mutant Y99C guanylate cyclase activating protein (GCAP)-1, to understand which effects arose from elevated dark levels of cGMP and Ca2+. Results: Except for PDE, transduction protein levels were normal in low-AIPL1 retinas, as were guanylate cyclase (GC), rhodopsin kinase (RK), and normalized phosphodiesterase (PDE) activities. Y99C and low-AIPL1 rods were more sensitive to flashes than normal, but flash responses of low-AIPL1 rods showed an abnormal delay, reduced rate of increase, and longer recovery not present in Y99C rod responses. In addition, low-AIPL1 rods but not Y99C rods failed to reach the normal light-induced minimum in Ca2+ concentration. Conclusions: Reduced AIPL1 delayed the photoresponse, decreased its amplification constant, slowed a rate-limiting step in its recovery, and limited the light-induced decrease in Ca2+. Not all changes were attributable to decreased PDE or to elevated cGMP and Ca2+ in darkness. Therefore, AIPL1 directly or indirectly affects more than one component of phototransduction.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Calcium/metabolism ; Carrier Proteins/physiology ; Chromatography, Gas ; Cyclic GMP/metabolism ; Electroretinography ; Fatty Acids/metabolism ; G-Protein-Coupled Receptor Kinase 1/metabolism ; Guanylate Cyclase/metabolism ; Guanylate Cyclase-Activating Proteins/metabolism ; Mice ; Mice, Transgenic ; Phosphoric Diester Hydrolases/metabolism ; Photic Stimulation ; Retinal Rod Photoreceptor Cells/physiology ; Retinal Rod Photoreceptor Cells/radiation effects ; Transducin/metabolism ; Vision, Ocular/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Aipl1 protein, mouse ; Carrier Proteins ; Fatty Acids ; Guanylate Cyclase-Activating Proteins ; Guca1a protein, mouse ; G-Protein-Coupled Receptor Kinase 1 (EC 2.7.11.14) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Transducin (EC 3.6.5.1) ; Guanylate Cyclase (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2006-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.05-1341
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Article: Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule

Kelton, Christie / Wesolowski, John S. / Soloviev, Maria / Schweickhardt, Rene / Fischer, David / Kurosawa, Emmi / McKenna, Sean D. / Gross, Alec W.

Archives of biochemistry and biophysics

Volume v. 526,, Issue no. 2

Abstract	Certain combinations of non-competitive anti-EGFR antibodies have been reported to produce new effects on cells compared to either antibody used separately. New and enhanced combination-activity includes increased inhibition of signaling, increased receptor internalization and degradation, reduced proliferation of tumor cell lines and induction of complement-dependent cytotoxicity (CDC) effector function. To test requirements and mechanisms to elicit enhanced combination-activity with different EGFR binding domains, we created an anti-EGFR biparatopic antibody. A biparatopic antibody interacts through two different antigen-binding sites to a single antigen. A heterodimeric antibody with one binding domain derived from the C225 antibody and one binding domain derived from the humanized 425 (hu425) antibody was built on the strand-exchange engineered domain (SEED) scaffold. This anti-EGFR biparatopic-SEED antibody was compared to parental antibodies used alone and in combination, and to the corresponding monovalent anti-EGFR-SEED antibodies used alone or in combination. We found that the anti-EGFR biparatopic-SEED had enhanced activity, similar to the combination of the two parental antibodies. Combinations of monovalent anti-EGFR-SEED antibodies did not produce enhanced effectiveness in cellular assays. Our results show that the anti-EGFR biparatopic antibody created using the SEED scaffold has enhanced combination-activity in a single molecule. Furthermore, these data suggest that the potential to cross-link the two different epitopes is an important requirement in the mechanism of enhanced combination-activity.
Keywords	epitopes ; antibodies ; cytotoxicity ; assays ; neoplasm cells ; cell lines
Language	English
Document type	Article
ISSN	0003-9861
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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