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1.
Drugs Today (Barc) ; 57(11): 653-663, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34821879

RESUMO

Multiple myeloma is the second most common hematologic malignancy worldwide. Despite the growing number of available therapeutic options and advances in the treatment since the 2000s, relapse of multiple myeloma is inevitable. Currently, the main therapeutic agents for multiple myeloma treatment include proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and others. Patients who relapse or are refractory to the above-mentioned treatments have poor prognosis. B-cell maturation antigen (BCMA) is a cell-surface receptor which is expressed on the membrane of multiple myeloma cells, but absent on naive and memory B cells, making it an ideal target for multiple myeloma treatment. Belantamab mafodotin (GSK-2857916) is a first-in-class BCMA antibody-drug conjugate with an overall response rate of 32% in the phase II clinical trial DREAMM-2, which is a phase II study designed to investigate the efficacy and safety of belantamab mafodotin in relapsed/refractory patients with multiple myeloma. In August 2020, based on the results of this pivotal DREAMM-2 study, the U.S. Food and Drug Administration (FDA) approved belantamab mafodotin as a monotherapy for relapsed/refractory multiple myeloma. Thereafter, the European Medicines Agency (EMA) also approved this indication. Although belantamab mafodotin has demonstrated single-agent activity in relapsed/refractory multiple myeloma, further studies to evaluate its efficacy and its combinational use with other drugs are necessary and ongoing.


Assuntos
Imunoconjugados , Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Humanos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia
2.
Anal Chim Acta ; 1183: 338987, 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34627511

RESUMO

The goal of the study was to evaluate the possibilities offered by a new generation of metal-free SEC column to perform direct SEC-MS of protein biopharmaceuticals using ammonium acetate as the main mobile phase additive. The prototype metal-free SEC column hardware used in this work was a polyether ether ketone (PEEK) infused stainless steel tube including PEEK frits. This PEEK-lined column provides a fully bioinert and metal-free fluidic path, while maintaining the stability of the metal hardware, and could be a good solution to limit possible undesired interactions between proteins and column wall/frits. This prototype metal-free SEC column was systematically compared with a conventional stainless-steel SEC column hardware packed with the same stationary phase material. Four different mAb products, namely trastuzumab, palivizumab, bevacizumab and NISTmAb, and one antibody drug conjugate (ADC), trastuzumab emtansine, were selected as test samples. It appears that peak symmetry, separation of low molecular weight species (LMWS), and the recovery of high molecular weight species (HMWS) were significantly improved for the different biopharmaceutical products on the metal-free SEC column. It has also been demonstrated that the largest differences between standard and metal-free SEC columns were observed for the most basic mAbs (high pI), which confirms that electrostatic interactions between the mAb and the metallic parts of the column (frits and inlet tube) could be responsible for the issues observed when performing SEC analysis with volatile mobile phase. Finally, it was feasible to perform SEC-MS analysis for a wide range of biopharmaceutical products using volatile mobile phase. Our results also highlight that an inappropriate column could bias the quantification of size variants when using MS-compatible mobile phases. Therefore, metal-free column, such as the PEEK-lined column, should be preferentially selected for SEC-MS analysis.


Assuntos
Imunoconjugados , Metais , Anticorpos Monoclonais , Cromatografia em Gel , Espectrometria de Massas
3.
Molecules ; 26(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34641391

RESUMO

The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market 'boom', garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed.


Assuntos
Antineoplásicos/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Aprovação de Drogas , Humanos , Estados Unidos , United States Food and Drug Administration
4.
Chem Pharm Bull (Tokyo) ; 69(10): 976-983, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602579

RESUMO

Antibody-drug conjugates (ADCs) are biopharmaceuticals produced by chemically linking small molecules (payloads) to antibodies that possess specific affinity for the target cell. The ADCs currently on the commercially market are the result of a stochastic conjugation of highly-potent payloads to multiple sites on the monoclonal antibody, resulting in a heterogeneous drug-antibody ratio (DAR) and drug distribution. The heterogeneity inherent to ADCs not produced site-specifically may not only be detrimental to the quality of the drug but also is less-desirable from the perspective of regulatory science. An ideal method or unified approach used to measure the DAR for ADCs, a critical aspect of their analysis and characterization, has not yet been established in the ADC field and remains an often-challenging issue for bioanalytical chemists. In this review we describe, compare, and evaluate the characteristics of various DAR determination methods for ADCs featuring recently reported technologies. The future landscape of bioconjugate DAR analysis is also discussed.


Assuntos
Imunoconjugados/análise , Humanos , Estrutura Molecular
5.
Nanoscale ; 13(41): 17648-17654, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34664606

RESUMO

Liposome-based immunoassay (LIA) is an attractive protocol for amplifying the detection signals because of the excellent ability of liposomes to encapsulate signal marker compounds. The antigen-binding activity of the conjugated antibodies on the liposomal surface is crucial for the specificity and sensitivity of LIA. We present here a general platform to ensure that antibodies can conjugate onto the surface of liposomes in a site-specific and oriented manner. A His-handle-modified antibody with Fc region-specific and covalent conjugation was first fabricated using a photoactivatable ZBpa-His tag that was engineered using the aminoacyl-tRNA synthetase/suppressor tRNA technique. Based on the high affinity between the His tag and divalent metal ions, the novel His-modified antibody was oriented onto the surface of nickel ion-modified liposomes encapsulating horseradish peroxidase. With the prostate-specific antigen as a model, the detection efficiency of the new immunoliposomes was evaluated by chemiluminescence immunoassay. The immunoliposomes exhibited a limit of detection of 0.2 pg mL-1, which was a six time improvement compared with that of the chemical-coupled antibody-liposome conjugates. Thus, the proposed immunoliposomes are expected to hold potential applications for the sensitive detection of various biomarkers in complicated serum samples.


Assuntos
Imunoconjugados , Lipossomos , Anticorpos , Antígenos , Humanos , Imunoensaio , Masculino
6.
Molecules ; 26(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641586

RESUMO

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is 177Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.


Assuntos
Antineoplásicos/uso terapêutico , Citotoxinas/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Imunoconjugados/uso terapêutico , Neoplasias/terapia , Peptídeos/uso terapêutico , Radioterapia/métodos , Portadores de Fármacos/química , Desenho de Fármacos , Humanos , Melfalan/análogos & derivados , Melfalan/uso terapêutico , Peptídeos/química , Preparações Farmacêuticas/química , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Somatostatina/uso terapêutico
7.
MAbs ; 13(1): 1974150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34486490

RESUMO

This study describes the characterization of conjugation sites for a random, lysine conjugated 2-iminothiolane (2-IT) based antibody-drug-conjugate synthesized from an IgG1 antibody and a duocarmycin analog-based payload-linker. Of the 80 putative lysine sites, 78 were found to be conjugated via tryptic peptide mapping and LC-HRMS. Surprisingly, seven cysteine-linked conjugated peptides were also detected resulting from the conjugation of cysteine residues derived from the four inter-chain disulfide bonds during the reaction. This unexpected finding could be attributed to the free thiols of the 2-IT thiolated antibody intermediates and/or the 4-mercaptobutanamide by-product resulting from the hydrolysis of 2-IT. These free thiols could cause the four inter-chain disulfide bonds of the antibody to scramble via intra- or inter-molecular attack. The presence of only pair of non-reactive (unconjugated) lysine residues, along with the four intact intra-chain disulfide bonds, is attributed to their poor accessibility, which is consistent with solvent accessibility modeling analysis. We also discovered a major by-product derived from the hydrolysis of the amidine moiety of the N-terminus conjugate. In contrast, the amidine moiety in lysine-linked conjugates appeared stable. Based on our results, we propose plausible formation mechanisms of cysteine-linked conjugates and the hydrolysis of the N-terminus conjugate, which provide scientific insights that are beneficial to process development and drug quality control.


Assuntos
Cisteína/química , Descoberta de Drogas/métodos , Imunoconjugados/química , Lisina/química , Duocarmicinas/análogos & derivados , Humanos , Imunoglobulina G/química
8.
Nat Commun ; 12(1): 5577, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552066

RESUMO

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfoma Anaplásico de Células Grandes/genética , Receptores de Interleucina-2/genética , Proteínas Repressoras/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoconjugados/farmacologia , Interleucina-15/farmacologia , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Antígeno Ki-1/genética , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Sequências Reguladoras de Ácido Nucleico , Proteínas Repressoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Future Oncol ; 17(30): 3911-3924, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467774

RESUMO

Sacituzumab Govitecan (also known by the brand name TRODELVY®) is a new and available treatment for metastatic triple-negative breast cancer, or mTNBC for short. Metastatic breast cancer means the breast cancer has spread to other parts of the body. Triple negative means the breast cancer does not have 3 common proteins on the cell surface called receptors. This is a summary of the ASCENT study, published in the New England Journal of Medicine in April 2021. This study compared Sacituzumab Govitecan with standard chemotherapy. Chemotherapy is a treatment that kills cancer cells or stops them from dividing. 529 people with mTNBC took part in the study across 7 countries. All who took part had already received 2 previous chemotherapies, which stopped working for their cancer. The study showed that patients who took Sacituzumab Govitecan lived longer than those who took a different chemotherapy while on the study. Tumors shrank in more patients who took Sacituzumab Govitecan than in patients who took chemotherapy. In general, patients who took Sacituzumab Govitecan experienced more side effects. This included low levels of a type of white blood cell known as neutrophils (neutropenia) and loose or watery stool (diarrhea). Use of supportive care lessened these side effects. This summary also includes insights and perspectives from 2 breast cancer patient advocates. ClinicalTrials.gov NCT number: NCT02574455. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here.


Assuntos
Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Camptotecina/análogos & derivados , Humanos , Idioma , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
10.
Talanta ; 235: 122773, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34517630

RESUMO

The human epidermal growth factor receptor 2 (HER2) is a transmembrane protein that has become one of the most specific prognostic and predictive biomarker of breast cancer. Its early detection is key for optimizing the patient clinical outcome. This work is focused on the detection of HER2 in individual cells using an antibody containing lutetium (Lu) as reporter group that is monitored by introducing the individual cells into the inductively coupled plasma mass spectrometer (ICP-MS). This Lu-containing antibody probe is used to label different breast cancer cell lines considered HER2 negative (MDA-MB-231) and positive (SKBR-3 and BT-474). Optimizations regarding the amount of the probe necessary to ensure complete labelling reactions are conducted in the different cell models. Concentrations in the range of 0.006 fg Lu/cell and 0.030 fg Lu/cell could be found in the HER2 negative and HER2 positive cells, respectively. In addition, the selectivity of the labelling reaction is tested by using two different metal-containing antibody probes for HER2 (containing Lu) and for transferrin receptor 1 (containing Nd), respectively, within the same cell population. Finally, the methodology is applied to the targeting of HER2 positive cells in complex cell mixtures containing variable amounts of BT-474 and MDA-MB-231 cells. The obtained results showed the excellent capabilities of the proposed strategy to discriminate among cell populations. This finding could help for scoring HER2 positive tumors improving existing technologies.


Assuntos
Neoplasias da Mama , Imunoconjugados , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Linhagem Celular Tumoral , Feminino , Humanos , Lutécio , Prognóstico , Receptor ErbB-2
11.
Anal Chem ; 93(38): 12930-12937, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34519496

RESUMO

The therapeutic efficacy and pharmacokinetics of antibody-drug conjugates (ADCs) in general, and antibody-oligonucleotide conjugates (AOCs) in particular, depend on the drug-to-antibody ratio (DAR) distribution and average value. The DAR is considered a critical quality attribute, and information pertaining to it needs to be gathered during ADC/AOC development, production, and storage. However, because of the high structural complexity of ADC/AOC samples, particularly in the initial drug-development stages, the application of the current state-of-the-art mass spectrometric approaches can be limited for DAR analysis. Here, we demonstrate a novel approach for the analysis of complex ADC/AOC samples, following native size-exclusion chromatography Orbitrap Fourier transform mass spectrometry (FTMS). The approach is based on the integration of the proteoform-level mass spectral peaks in order to provide an estimate of the DAR distribution and its average value with less than 10% error. The peak integration is performed via a truncation of the Orbitrap's unreduced time-domain ion signals (transients) before mass spectra generation via FT processing. Transient recording and processing are undertaken using an external data acquisition system, FTMS Booster X2, coupled to a Q Exactive HF Orbitrap FTMS instrument. This approach has been applied to the analysis of whole and subunit-level trastuzumab conjugates with oligonucleotides. The obtained results indicate that ADC/AOC sample purification or simplification procedures, for example, deglycosylation, could be omitted or minimized prior to the DAR analysis, streamlining the drug-development process.


Assuntos
Imunoconjugados , Preparações Farmacêuticas , Análise de Fourier , Imunoconjugados/análise , Espectrometria de Massas , Oligonucleotídeos
12.
Oncol Res Treat ; 44(10): 547-556, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34515215

RESUMO

PURPOSE: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). EXPERIMENTAL DESIGN: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. RESULTS: Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. CONCLUSIONS: Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Imunoconjugados , Neoplasias Renais , Neoplasias , Neoplasias Ovarianas , Antineoplásicos/efeitos adversos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico
13.
Anal Chem ; 93(40): 13505-13512, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34585915

RESUMO

Monoclonal antibodies (mAbs) and related products undergo a wide range of modifications, many of which can often be directly associated to culture conditions during upstream processing. Ideally, such conditions should be monitored and fine-tuned based on real-time or close to real-time information obtained by the assessment of the product quality attribute (PQA) profile of the biopharmaceutical produced, which is the fundamental idea of process analytical technology. Therefore, methods that are simple, quick and robust, but sufficiently powerful, to allow for the generation of a comprehensive picture of the PQA profile of the protein of interest are required. A major obstacle for the analysis of proteins directly from cultures is the presence of impurities such as cell debris, host cell DNA, proteins and small-molecule compounds, which usually requires a series of capture and polishing steps using affinity and ion-exchange chromatography before characterization can be attempted. In the current study, we demonstrate direct coupling of protein A affinity chromatography with native mass spectrometry (ProA-MS) for development of a robust method that can be used to generate information on the PQA profile of mAbs and related products in as little as 5 min. The developed method was applied to several samples ranging in complexity and stability, such as simple and more complex monoclonal antibodies, as well as cysteine-conjugated antibody-drug conjugate mimics. Moreover, the method demonstrated suitability for the analysis of protein amounts of <1 µg, which suggests applicability during early-stage development activities.


Assuntos
Imunoconjugados , Proteína Estafilocócica A , Anticorpos Monoclonais , Cromatografia por Troca Iônica , Imunoconjugados/análise , Espectrometria de Massas
14.
Anal Biochem ; 632: 114384, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34543643

RESUMO

Invasive pulmonary aspergillosis (IPA) is a severe life-threatening condition. Diagnosis of fungal disease in general, and especially that caused by Aspergillus fumigatus is problematic. A. fumigatus secretes siderophores to acquire iron during infection, which are also essential for virulence. We describe the chemoacetylation of ferrated fusarinine C to diacetylated fusarinine C (DAFC), followed by protein conjugation, which facilitated triacetylfusarinine C (TAFC)-specific monoclonal antibody production with specific recognition of the ferrated form of TAFC. A single monoclonal antibody sequence was ultimately elucidated by a combinatorial strategy involving protein LC-MS/MS, cDNA sequencing and RNAseq. The resultant murine IgG2a monoclonal antibody was secreted in, and purified from, mammalian cell culture (5 mg) and demonstrated to be highly specific for TAFC detection by competitive ELISA (detection limit: 15 nM) and in a lateral flow test system (detection limit: 3 ng), using gold nanoparticle conjugated- DAFC-bovine serum albumin for competition. Overall, this work reveals for the first time a recombinant TAFC-specific monoclonal antibody with diagnostic potential for IPA diagnosis in traditional and emerging patient groups (e.g., COVID-19) and presents a useful strategy for murine Ig sequence determination, and expression in HEK293 cells, to overcome unexpected limitations associated with aberrant or deficient murine monoclonal antibody production.


Assuntos
Anticorpos Monoclonais/imunologia , Aspergilose/diagnóstico , Compostos Férricos/imunologia , Ácidos Hidroxâmicos/imunologia , Imunoconjugados/química , Sideróforos/química , Animais , Aspergilose/microbiologia , Aspergillus fumigatus/química , Aspergillus fumigatus/patogenicidade , Ensaio de Imunoadsorção Enzimática , Compostos Férricos/análise , Células HEK293 , Humanos , Ácidos Hidroxâmicos/análise , Camundongos , Proteínas Recombinantes/imunologia
15.
Am J Physiol Cell Physiol ; 321(5): C846-C858, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34550795

RESUMO

Glypican-1 (GPC1) is one of the six glypican family members in humans. It is composed of a core protein with three heparan sulfate chains and attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. GPC1 modulates various signaling pathways including fibroblast growth factors (FGF), vascular endothelial growth factor-A (VEGF-A), transforming growth factor-ß (TGF-ß), Wnt, Hedgehog (Hh), and bone morphogenic protein (BMP) through specific interactions with pathway ligands and receptors. The impact of these interactions on signaling pathways, activating or inhibitory, is dependent upon specific GPC1 domain interaction with pathway components, as well as cell surface context. In this review, we summarize the current understanding of the structure of GPC1, as well as its role in regulating multiple signaling pathways. We focus on the functions of GPC1 in cancer cells and how new insights into these signaling processes can inform its translational potential as a therapeutic target in cancer.


Assuntos
Glipicanas/metabolismo , Transdução de Sinais , Animais , Antineoplásicos Imunológicos/uso terapêutico , Glipicanas/antagonistas & inibidores , Glipicanas/química , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia Adotiva , Ligantes , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Conformação Proteica , Relação Estrutura-Atividade
16.
17.
Lancet Haematol ; 8(11): e794-e807, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34529955

RESUMO

BACKGROUND: Indatuximab ravtansine (BT062) is an antibody-drug conjugate that binds to CD138 and synergistically enhances the antitumor activity of lenalidomide in preclinical models of multiple myeloma. This phase 1/2a study was done to determine the safety, activity, and pharmacokinetics of indatuximab ravtansine in combination with immunomodulatory drugs in patients with relapsed or refractory multiple myeloma. METHODS: This open-label, phase 1/2a study took place at nine hospital sites in the USA. Eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and ECOG performance status or Zubrod score of 2 or below. Patients who received indatuximab ravtansine with lenalidomide and dexamethasone (indatuximab ravtansine plus lenalidomide) had failure of at least one previous therapy. Patients treated with indatuximab ravtansine with pomalidomide and dexamethasone (indatuximab ravtansine plus pomalidomide) had failure of at least two previous therapies (including lenalidomide and bortezomib) and had progressive disease on or within 60 days of completion of their last treatment. In phase 1, patients received indatuximab ravtansine intravenously on days 1, 8, and 15 of each 28-day cycle in escalating dose levels of 80 mg/m2, 100 mg/m2, and 120 mg/m2, with lenalidomide (25 mg; days 1 to 21 every 28 days orally) and dexamethasone (20-40 mg; days 1, 8, 15, and 22 every 28 days). In phase 2, the recommended phase 2 dose of indatuximab ravtansine was given to an expanded cohort of patients in combination with lenalidomide and dexamethasone. The protocol was amended to allow additional patients to be treated with indatuximab ravtansine plus pomalidomide (4 mg; days 1 to 21 every 28 days orally) and dexamethasone, in a more heavily pretreated patient population than in the indatuximab ravtansine plus lenalidomide group. The phase 1 primary endpoint was to determine the dose-limiting toxicities and the maximum tolerated dose (recommended phase 2 dose) of indatuximab ravtansine, and the phase 2 primary endpoint was to describe the objective response rate (ORR; partial response or better) and clinical benefit response (ORR plus minor response). All patients were analysed for safety and all patients with post-treatment response assessments were analysed for activity. This study is registered with ClinicalTrials.gov, number NCT01638936, and is complete. FINDINGS: 64 (86%) of 74 screened patients were enrolled between July 3, 2012, and June 30, 2015. 47 (73%) patients received indatuximab ravtansine plus lenalidomide (median follow-up 24·2 months [IQR 19·9-45·4]) and 17 (27%) received indatuximab ravtansine plus pomalidomide (24·1 months [17·7-36·7]). The maximum tolerated dose of indatuximab ravtansine plus lenalidomide was 100 mg/m2, and defined as the recommended phase 2 dose for indatuximab ravtansine plus pomalidomide. An objective response for indatuximab ravtansine plus lenalidomide was observed in 33 (71·7%) of 46 patients and in 12 (70·6%) of 17 patients in the indatuximab ravtansine plus pomalidomide group. The clinical benefit response for indatuximab ravtansine plus lenalidomide was 85% (39 of 46 patients) and for indatuximab ravtansine plus pomalidomide it was 88% (15 of 17 patients). The most common grade 3-4 adverse events in both groups were neutropenia (14 [22%] of 64 patients), anaemia (10 [16%]), and thrombocytopenia (seven [11%]). Treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 35 (55%) of the 64 patients. Five (8%) patients with a TEAE had a fatal outcome; none was reported as related to indatuximab ravtansine. INTERPRETATION: Indatuximab ravtansine in combination with immunomodulatory drugs shows preliminary antitumor activity, is tolerated, and could be further evaluated in patients with relapsed or refractory multiple myeloma. FUNDING: Biotest AG.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Imunoconjugados/uso terapêutico , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Lenalidomida/efeitos adversos , Masculino , Dose Máxima Tolerável , Maitansina/efeitos adversos , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/uso terapêutico
18.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575942

RESUMO

Colorectal cancer (CRC) is an aggressive cancer that remains a challenge to diagnose and treat. Photodynamic diagnosis (PDD) and therapy (PDT) are novel alternative techniques, which can enhance early diagnosis, as well as elicit tumor cell death. This is accomplished through photosensitizer (PS) mediated fluorescence and cytotoxic reactive oxygen species activation upon laser light irradiation excitation at specific low and high range wavelengths, respectively. However, the lack of PS target tumor tissue specificity often hampers these techniques. This study successfully fabricated a bioactive nanoconjugate, ZnPcS4-AuNP-S-PEG5000-NH2-Anti-GCC mAb (BNC), based upon a polyethylene glycol-gold nanoparticle, which was multi-functionalized with a fluorescent PDT metalated zinc phthalocyanine PS, and specific anti-GCC targeting antibodies, to overcome CRC PDD and PDT challenges. The BNC was found to be stable and showed selectively improved subcellular accumulation within targeted CRC for improved PDD and PDT outcomes in comparison to healthy in vitro cultured cells. Additionally, the BNC reported significantly higher late apoptotic PDT-induced CRC cell death rates (34% ***) when compared to PDT PS administration alone (15% *). These results indicated that the improved PDD and PDT outcomes were due to the specific PS accumulation in CRC cells through nanoparticle carriage and bioactive anti-GCC targeting.


Assuntos
Neoplasias Colorretais/terapia , Imunoconjugados/farmacologia , Imunoterapia , Nanopartículas Metálicas/uso terapêutico , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Ouro/química , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Indóis/química , Indóis/farmacologia , Nanopartículas Metálicas/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo
19.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361793

RESUMO

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.


Assuntos
Antineoplásicos/química , Química Click/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Radiossensibilizantes/química , Radioimunoterapia/métodos , Alcinos/química , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Azidas/química , Reação de Cicloadição/métodos , Ciclo-Octanos/química , Elétrons , Compostos Heterocíclicos com 1 Anel/química , Humanos , Concentração de Íons de Hidrogênio , Imunoconjugados/química , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Neoplasias/química , Neoplasias/imunologia , Neoplasias/patologia , Fotoquimioterapia/métodos , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/farmacologia
20.
Crit Rev Oncol Hematol ; 166: 103453, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34461271

RESUMO

B-cell maturation antigen (BCMA) has become a key target for antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T-cell therapies, and other immunotherapies in multiple myeloma. Some of these agents such as belantamab mafodotin and idecabtagene vicleucel have already received regulatory approval in the United States. Although BCMA has generally been considered to be expressed almost exclusively in plasma cells with a low likelihood of on-target off-tumor toxicity, there has been a range of unusual neurotoxicity observed across the spectrum of BCMA immunotherapies. In certain cases, these unusual neurotoxicity presentations have led to patient death or withdrawal of agents from further development. Our review summarizes the literature in this field and highlights the possibility of on-target toxicities due to neural expression of BCMA. We draw attention to the need for further investigation of these toxicities. This risk becomes increasingly important as BCMA targeted therapies are brought to earlier lines of treatment.


Assuntos
Anticorpos Biespecíficos , Imunoconjugados , Mieloma Múltiplo , Antígeno de Maturação de Linfócitos B , Humanos , Imunoterapia Adotiva , Mieloma Múltiplo/tratamento farmacológico
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