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Pesquisa : D12.776.124.486.485.114.125 [Categoria DeCS]
Referências encontradas : 1731 [refinar]
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  1 / 1731 MEDLINE  
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PMID:29357376
Autor:Li Y; Zhou C; Li J; Liu J; Lin L; Li L; Cao D; Li Q; Wang Z
Endereço:School of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Guangzhou, China.
Título:Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells.
Fonte:PLoS One; 13(1):e0191024, 2018.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Muc1 is one of the most studied tumor antigens. However, antibodies or antibody-toxin conjugates against Muc1 have not shown significant efficacy for tumors with Muc1 overexpression. In this study, we employed bispecific antibody approach to target Muc1 positive tumor cells. A novel bispecific antibody, Muc1-Bi-1, was constructed by linking single domain antibodies, anti-Muc1-VHH and anti-CD16-VHH. Muc1-Bi-2, the humanized form of Muc1-Bi-1, was also constructed by grafting. Both Muc1-Bi bispecific antibodies can be efficiently expressed and purified from bacteria. In vitro, the Muc1-Bi bispecific antibodies can recruit Natural Killer (NK) cells to drive potent and specific cell killing of Muc1-overexpressing tumor cells. In xenograft model, the Muc1-Bi bispecific antibodies can suppress tumor growth in the presence of human peripheral blood mononuclear cells (PBMC). These data suggested that the single domain based Muc1-Bi may provide a valid strategy for targeting tumors with Muc1 overexpression.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Antibodies, Bispecific); 0 (MUC1 protein, human); 0 (Mucin-1)


  2 / 1731 MEDLINE  
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PMID:29228299
Autor:Goicochea NL; Garnovskaya M; Blanton MG; Chan G; Weisbart R; Lilly MB
Endereço:Department of Medicine, Division of Hematology/Oncology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St., Charleston, SC 29425, USA.
Título:Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy.
Fonte:Protein Eng Des Sel; 30(12):785-793, 2017 12 01.
ISSN:1741-0134
País de publicação:England
Idioma:eng
Resumo:Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10-AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand-independent manner. It may be an attractive prototype agent for prostate cancer therapy.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (AR protein, human); 0 (Antibodies, Bispecific); 0 (Receptors, Androgen)


  3 / 1731 MEDLINE  
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PMID:29366356
Autor:Godar M; de Haard H; Blanchetot C; Rasser J
Endereço:a argenx BVBA , Zwijnaarde , Belgium.
Título:Therapeutic bispecific antibody formats: a patent applications review (1994-2017).
Fonte:Expert Opin Ther Pat; 28(3):251-276, 2018 Mar.
ISSN:1744-7674
País de publicação:England
Idioma:eng
Resumo:INTRODUCTION: Bispecific antibodies have become increasingly of interest by enabling new therapeutic applications such as retargeting cellular immunity towards tumor cells. About 23 bispecific antibody platforms have therefore been developed, generating about 62 molecules which are currently being evaluated for potential treatment of a variety of indications, such as cancer and inflammatory diseases, among which three molecules were approved. This class of drugs will represent a multi-million-dollar market over the coming years. Many companies have consequently invested in the development of bispecific antibody platforms, creating an important patent activity in this field. Areas covered: The present review gives an overview of the patent literature over the period 1994-2017 of different immunoglobulin gamma-based bispecific antibody platforms and the molecules approved or in clinical trials. Expert opinion: Bispecific antibodies are progressively accepted as potentially superior therapeutic molecules in a broad range of diseases. This frantic activity creates a maze of hundreds of patents that pose considerable legal risks for both newcomers and established companies. It can consecutively be anticipated that the number of patent conflicts will increase. Nevertheless, it can be expected that patents related to the use of a bispecific antibody will have tremendous commercial value.
Tipo de publicação: JOURNAL ARTICLE; REVIEW
Nome de substância:0 (Antibodies, Bispecific); 0 (Antineoplastic Agents); 0 (Immunoglobulin G)


  4 / 1731 MEDLINE  
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PMID:28450393
Autor:Skegro D; Stutz C; Ollier R; Svensson E; Wassmann P; Bourquin F; Monney T; Gn S; Blein S
Endereço:From the Department of Antibody Engineering, Biologics Research, Glenmark Pharmaceuticals S.A., Chemin de la Combeta 5, 2300 La Chaux-de-Fonds, Switzerland and.
Título:Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies.
Fonte:J Biol Chem; 292(23):9745-9759, 2017 06 09.
ISSN:1083-351X
País de publicação:United States
Idioma:eng
Resumo:Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains. The method can be applied across Igs to design Fc heterodimers and bsAbs. We investigated interfaces from human IgA CH3, IgD CH3, IgG1 CH3, IgM CH4, T-cell receptor (TCR) α/ß, and TCR γ/δ constant domain pairs, and we found that they successfully drive human IgG1 CH3 or IgM CH4 heterodimerization to levels similar to or above those of reference methods. A comprehensive interface exchange between the TCR α/ß constant domain pair and the IgG1 CH3 homodimer was evidenced by X-ray crystallography and used to engineer examples of bsAbs for cancer therapy. Parental antibody pairs were rapidly reformatted into scalable bsAbs that were free of homodimer traces by combining interface exchange, asymmetric Protein A binding, and the scFv × Fab format. In summary, we successfully built several new CH3- or CH4-based heterodimers that may prove useful for designing new bsAb-based therapeutics, and we anticipate that our approach could be broadly implemented across the Ig constant domain family. To our knowledge, CH4-based heterodimers have not been previously reported.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antibodies, Bispecific); 0 (Immunoglobulin A); 0 (Immunoglobulin Fc Fragments); 0 (Immunoglobulin G); 0 (Immunoglobulin M)


  5 / 1731 MEDLINE  
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PMID:29188947
Autor:Wada H; Matsumoto T; Katayama N
Endereço:Mie University Graduate School of Medicine, Tsu, Japan
Título:Emicizumab Prophylaxis in Hemophilia A with Inhibitors.
Fonte:N Engl J Med; 377(22):2193-4, 2017 11 30.
ISSN:1533-4406
País de publicação:United States
Idioma:eng
Tipo de publicação: LETTER; COMMENT
Nome de substância:0 (Antibodies, Bispecific); 0 (Antibodies, Monoclonal, Humanized); 0 (emicizumab)


  6 / 1731 MEDLINE  
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PMID:29188944
Autor:Aledort LM; Ewenstein BM
Título:Emicizumab Prophylaxis in Hemophilia A with Inhibitors.
Fonte:N Engl J Med; 377(22):2193, 2017 11 30.
ISSN:1533-4406
País de publicação:United States
Idioma:eng
Tipo de publicação: LETTER; COMMENT
Nome de substância:0 (Antibodies, Bispecific); 0 (Antibodies, Monoclonal, Humanized); 0 (emicizumab)


  7 / 1731 MEDLINE  
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PMID:28873441
Autor:Robert R; Juglair L; Lim EX; Ang C; Wang CJH; Ebert G; Dolezal O; Mackay CR
Endereço:Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Título:A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6.
Fonte:PLoS One; 12(9):e0184278, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antibodies, Bispecific); 0 (Antibodies, Monoclonal); 0 (Immunoglobulin G); 0 (Receptors, CCR6); 0 (Receptors, CXCR3)


  8 / 1731 MEDLINE  
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PMID:28864715
Autor:van Gils MJ; Sanders RW
Endereço:From the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands and m.j.vangils@amc.uva.nl.
Título:Opposites attract in bispecific antibody engineering.
Fonte:J Biol Chem; 292(35):14718-14719, 2017 09 01.
ISSN:1083-351X
País de publicação:United States
Idioma:eng
Resumo:Bispecific antibodies show great promise as intrinsic combination therapies, but often suffer from poor physiochemical properties, many times related to poor heterodimerization. De Nardis identify specific electrostatic interactions that facilitate efficient heterodimerization, resulting in bispecific antibodies with physiochemical properties very similar to those of naturally occurring antibodies. This provides a new platform for the treatment of an array of diseases from cancer and autoimmune diseases to infectious diseases.
Tipo de publicação: JOURNAL ARTICLE; COMMENT
Nome de substância:0 (Antibodies, Bispecific)


  9 / 1731 MEDLINE  
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PMID:28837681
Autor:Ross SL; Sherman M; McElroy PL; Lofgren JA; Moody G; Baeuerle PA; Coxon A; Arvedson T
Endereço:Department of Oncology Research, Amgen Inc., Thousand Oaks, California, United States of America.
Título:Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing.
Fonte:PLoS One; 12(8):e0183390, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:For targets that are homogenously expressed, such as CD19 on cells of the B lymphocyte lineage, immunotherapies can be highly effective. Targeting CD19 with blinatumomab, a CD19/CD3 bispecific antibody construct (BiTE®), or with chimeric antigen receptor T cells (CAR-T) has shown great promise for treating certain CD19-positive hematological malignancies. In contrast, solid tumors with heterogeneous expression of the tumor-associated antigen (TAA) may present a challenge for targeted therapies. To prevent escape of TAA-negative cancer cells, immunotherapies with a local bystander effect would be beneficial. As a model to investigate BiTE®-mediated bystander killing in the solid tumor setting, we used epidermal growth factor receptor (EGFR) as a target. We measured lysis of EGFR-negative populations in vitro and in vivo when co-cultured with EGFR-positive cells, human T cells and an EGFR/CD3 BiTE® antibody construct. Bystander EGFR-negative cells were efficiently lysed by BiTE®-activated T cells only when proximal to EGFR-positive cells. Our mechanistic analysis suggests that cytokines released by BiTE®-activated T-cells induced upregulation of ICAM-1 and FAS on EGFR-negative bystander cells, contributing to T cell-induced bystander cell lysis.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antibodies, Bispecific); 0 (Cytokines); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)


  10 / 1731 MEDLINE  
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PMID:28825327
Autor:Wilke AC; Gökbuget N
Endereço:a University Hospital , Department of Medicine II , Frankfurt , Germany.
Título:Clinical applications and safety evaluation of the new CD19 specific T-cell engager antibody construct blinatumomab.
Fonte:Expert Opin Drug Saf; 16(10):1191-1202, 2017 Oct.
ISSN:1744-764X
País de publicação:England
Idioma:eng
Resumo:INTRODUCTION: Blinatumomab is a T-cell engager antibody construct with dual specificity for CD19 and CD3, inducing serial lysis of CD19 positive B cells by redirecting cytotoxic T cells. It has been approved for the indication of Ph chromosome negative relapsed or refractory B-acute lymphoblastic leukemia (ALL), but has also been tested in ALL with minimal residual disease, relapsed Ph/BCR-ABL positive ALL, relapsed ALL in pediatric patients and relapsed or refractory non-Hodgkin's lymphoma (NHL). Adverse events have been mainly related to infection and hematological toxicities, as well as cytokine release syndrome and neurotoxicity. Areas covered: The review will discuss mechanisms of action, published literature on efficacy in ALL and NHL, specific aspects of administration, frequent adverse events and practical management. Expert opinion: Blinatumomab represents an effective new treatment for highly resistant relapsed/refractory B-precursor ALL. Practical handling bears challenges due to application as four week continous infusion and specific adverse effects which can be well handled by experienced centers. Most promising outcomes are reported for patients with resistant disease but lower tumor load such as MRD positive ALL patients. Future studies will focus on the use of blinatumomab during first-line therapy and the role of stem cell transplantation after blinatumomab treatment.
Tipo de publicação: JOURNAL ARTICLE; REVIEW
Nome de substância:0 (Antibodies, Bispecific); 0 (Antigens, CD19); 0 (Antineoplastic Agents); 4FR53SIF3A (blinatumomab)



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