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1.
Clin. transl. oncol. (Print) ; 24(6): 981-996, junio 2022.
Artigo em Inglês | IBECS | ID: ibc-203801

RESUMO

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody–drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.


Assuntos
Humanos , Adenocarcinoma/tratamento farmacológico , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
2.
Pharmacol Rev ; 74(3): 680-711, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35710136

RESUMO

Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a "magic bullet" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Microambiente Tumoral
3.
Mol Cancer Ther ; 21(6): 986-998, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35642431

RESUMO

In the past year, four antibody-drug conjugates (ADC) were approved, nearly doubling the marketed ADCs in oncology. Among other attributes, successful ADCs optimize targeting antibody, conjugation chemistry, and payload mechanism of action. Here, we describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for the treatment of small cell lung cancer (SCLC). We engineered a calicheamicin conjugate that lacks the acid-labile hydrazine linker that leads to systemic release of a toxic catabolite. We then screened a patient-derived xenograft library to identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs. Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, we identified seizure-related homolog 6 (SEZ6) as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression by both RNA-seq and IHC. We developed an antibody targeting SEZ6 that is rapidly internalized upon receptor binding and, when conjugated to the calicheamicin linker drug, drives potent tumor regression in vitro and in vivo. These preclinical data suggest that ABBV-011 may provide a novel treatment for patients with SCLC and a rationale for ongoing phase I studies (NCT03639194).


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antineoplásicos/farmacologia , Calicheamicinas , Ensaios Clínicos Fase I como Assunto , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
4.
Am J Clin Oncol ; 45(7): 279-285, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35728046

RESUMO

Trophoblast cell-surface antigen-2 (Trop-2) is a transmembrane calcium signal transducer and its overexpression is common in many types of malignant epithelial tumors, including breast cancer (BC). Sacituzumab govitecan-hziy (SG), the anti-Trop-2 antibody-drug conjugate, resulted in a significant survival benefit over chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC). The greatest efficacy was observed in those who had a medium or high Trop-2 score. However, the importance of Trop-2 as a potential predictive factor requires further research. Elderly patients also appear to benefit from treating with SG. While the early results are encouraging, the ultimate benefit of SG in patients with brain metastases has yet to be determined. Early phase studies have shown that SG is also active in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic BC. The most common side effects of SG are nausea, neutropenia and diarrhea. Currently, several clinical trials are in progress with SG in monotherapy and in combination treatment for various types of BC. Taken together, SG should be considered as a new standard of care in patients with pretreated mTNBC. This review summarizes the development and highlights recent advances of the SG in BC.


Assuntos
Imunoconjugados , Neoplasias de Mama Triplo Negativas , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia
5.
Cell Rep Med ; 3(6): 100668, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732147

RESUMO

In DESTINY-Breast 03, Trastuzumab Deruxtecan, a HER2-specific antibody-drug conjugate, proved superior to T-DM1 in patients with HER2+ metastatic breast cancer progressing on taxane and trastuzumab.1 This study supported its recent approval as second-line therapy in HER2+ metastatic breast cancer.


Assuntos
Neoplasias da Mama , Imunoconjugados , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Feminino , Humanos , Imunoconjugados/uso terapêutico , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêutico
6.
Bioconjug Chem ; 33(6): 1210-1221, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35658441

RESUMO

Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a new mode of action for cancer-targeting antibody-drug conjugates (ADCs) with activity also in slowly proliferating cells. To extend the repertoire of available effector chemistries, we have developed a novel structural class of NAMPT inhibitors as ADC payloads. A structure-activity relationship-driven approach supported by protein structural information was pursued to identify a suitable attachment point for the linker to connect the NAMPT inhibitor with the antibody. Optimization of scaffolds and linker structures led to highly potent effector chemistries which were conjugated to antibodies targeting C4.4a (LYPD3), HER2 (c-erbB2), or B7H3 (CD276) and tested on antigen-positive and -negative cancer cell lines. Pharmacokinetic studies, including metabolite profiling, were performed to optimize the stability and selectivity of the ADCs and to evaluate potential bystander effects. Optimized NAMPTi-ADCs demonstrated potent in vivo antitumor efficacy in target antigen-expressing xenograft mouse models. This led to the development of highly potent NAMPT inhibitor ADCs with a very good selectivity profile compared with the corresponding isotype control ADCs. Moreover, we demonstrate─to our knowledge for the first time─the generation of NAMPTi payload metabolites from the NAMPTi-ADCs in vitro and in vivo. In conclusion, NAMPTi-ADCs represent an attractive new payload class designed for use in ADCs for the treatment of solid and hematological cancers.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígenos B7 , Linhagem Celular Tumoral , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Nicotinamida Fosforribosiltransferase , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
AAPS J ; 24(4): 73, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688991

RESUMO

Antibody-drug conjugates (ADCs) comprise 3 distinct parts: a specific antibody carrier (mAb), a linker, and a cytotoxic payload. Typical pharmacokinetic (PK) characterization of ADCs remains fragmented using separate noncompartmental analyses (NCA) of individual analytes, offering little insight into the dynamic relationships among the ADC components, and the safety and efficacy implications. As a result, it is exceedingly difficult to compare ADCs in terms of favorable PK characteristics. Therefore, there is a need for characterizing ADCs using the joint disposition properties critical for understanding the fate of an ADC complex and clinical implications. In this communication, we describe 3 joint disposition metrics (JDMs) for integrated NCA of ADCs based on a combination of common analytes of ADC, payload, conjugated payload, and total mAb. These JDMs were derived, each in a simple form of a ratio between appropriate PK parameters of two analytes, from the presumed drug delivery scheme behind typical ADC designs, in terms of (1) linker stability, (2) therapeutic exposure ratio, and (3) effective drug-to-antibody ratio in vivo. The validity of the JDM-based PK characterization was examined against model-based analyses via their applications to 3 clinical candidates: PF-06650808, PF-06647020, and PF-06664178. For instance, the linker stability estimates for PF-06650808, PF-06647020, and PF-06664178 were 0.31, 0.14, and 0.096, respectively, from the JDM-based analyses vs. 0.23, 0.11, and 0.086 by the model-based approach. Additionally, the JDMs were estimated for a number of FDA-approved or otherwise well-documented ADCs, showing their utilities in comparing ADCs in terms of favorable PK characteristics.


Assuntos
Antineoplásicos , Imunoconjugados , Antineoplásicos/farmacocinética , Imunoconjugados/farmacocinética
8.
Int J Mol Sci ; 23(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35682800

RESUMO

Triple-negative breast cancer (TNBC) is a group of heterogeneous and refractory breast cancers with the absence of estrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor 2 (HER2). Over the past decade, antibody drug conjugates (ADCs) have ushered in a new era of targeting therapy. Since the epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) are over expressed on triple-negative breast cancer, we developed novel ADCs by conjugating benzylguanine (BG)-modified monomethyl auristatin E (MMAE) to EpCAM- and EGFR-specific SNAP-tagged single chain antibody fragments (scFvs). Rapid and efficient conjugation was achieved by SNAP-tag technology. The binding and internalization properties of scFv-SNAP fusion proteins were confirmed by flow cytometry and fluorescence microscopy. The dose-dependent cytotoxicity was evaluated in cell lines expressing different levels of EGFR and EpCAM. Both ADCs showed specific cytotoxicity to EGFR or EpCAM positive cell lines via inducing apoptosis at a nanomolar concentration. Our study demonstrated that EGFR specific scFv-425-SNAP-BG-MMAE and EpCAM-specific scFv-EpCAM-SNAP-BG-MMAE could be promising ADCs for the treatment of TNBC.


Assuntos
Imunoconjugados , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial , Receptores ErbB/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo
11.
Target Oncol ; 17(3): 203-221, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35567672

RESUMO

Currently available treatment options for patients with refractory metastatic prostate, bladder, or kidney cancers are limited with the prognosis remaining poor. Advances in the pathobiology of tumors has led to the discovery of cancer antigens that may be used as the target for cancer treatment. Antibody-drug conjugates (ADCs) are a relatively new concept in cancer treatment that broaden therapeutic landscape. ADCs are examples of a 'drug delivery into the tumor' system composed of an antigen-directed antibody linked to a cytotoxic drug that may release cytotoxic components after binding to the antigen located on the surface of tumor cells. The clinical properties of drugs are influenced by every component of ADCs. Regarding uro-oncology, enfortumab vedotin (EV) and sacituzumab govitecan (SG) are currently registered for patients with locally advanced or metastatic urothelial cancer following previous treatment with an immune checkpoint inhibitor (iCPI; programmed death receptor-1 [PD-1] or programmed death-ligand 1 [PD-L1]) inhibitor) and platinum-containing chemotherapy. The EV-301 trial showed that EV significantly prolonged the overall survival compared with classic chemotherapy. The TROPHY-U-01 trial conducted to evaluate SG demonstrated promising results as regards the objective response rate and duration of response. The safety and efficacy of ADCs in monotherapy and polytherapy (mainly with iCPIs) for different cancer stages and tumor types are assessed in numerous ongoing clinical trials. The aim of this review is to present new molecular biomarkers, specific mechanisms of action, and ongoing clinical trials of ADCs in genitourinary cancers. In the expert discussion, we assess the place of ADCs in uro-oncology and discuss their clinical value.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Imunoconjugados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Masculino
12.
Expert Rev Hematol ; 15(6): 503-517, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35633050

RESUMO

INTRODUCTION: Immunotherapies targeting B cell maturation antigen (BCMA) in multiple myeloma are transitioning through trials and entering the clinic, and will likely become a core pillar in myeloma therapeutics. These agents demonstrate unprecedented activity in multiply relapsed patients, but notwithstanding the short follow-up times their survival curves do not appear to demonstrate a plateau, and the treatments inevitably bring with them a range of toxicities that might be associated with tolerability issues. AREAS COVERED: We will briefly lay out the current therapeutic landscape in multiple myeloma, before introducing BCMA and explaining its significance. We will address in turn the three key classes of anti-BCMA immunotherapies: antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells. We describe the mechanisms of action of these classes and review the evidence supporting their efficacy and toxicities. We then bring all three therapies into one discussion that explores how to mitigate toxicities and overcome myeloma's ability to resist these potent treatments. EXPERT OPINION: Finally, we take the discussion back to the clinic, and consider how we might deploy anti-BCMA therapies most effectively for our patients. We consider the sequencing of treatment, and what further evidence is needed to more fully inform our therapy decisions.


Assuntos
Anticorpos Biespecíficos , Imunoconjugados , Mieloma Múltiplo , Anticorpos Biespecíficos/efeitos adversos , Antígeno de Maturação de Linfócitos B , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia , Imunoterapia Adotiva , Mieloma Múltiplo/tratamento farmacológico
13.
Chem Soc Rev ; 51(10): 3886-3897, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35506708

RESUMO

Degrader-antibody conjugates (DACs) are novel entities that combine a proteolysis targeting chimera (PROTAC) payload with a monoclonal antibody via some type of chemical linker. This review provides a current summary of the DAC field. Many general aspects associated with the creation and biological performance of traditional cytotoxic antibody-drug conjugates (ADCs) are initially presented. These characteristics are subsequently compared and contrasted with related parameters that impact DAC generation and biological activity. Several examples of DACs assembled from both the scientific and the patent literature are utilized to highlight differing strategies for DAC creation, and specific challenges associated with DAC construction are documented. Collectively, the assembled examples demonstrate that biologically-active DACs can be successfully prepared using a variety of PROTAC payloads which employ diverse E3 ligases to degrade multiple protein targets.


Assuntos
Antineoplásicos , Imunoconjugados , Anticorpos Monoclonais , Proteólise
14.
Future Oncol ; 18(19): 2351-2360, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35510484

RESUMO

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable tetrapeptide-based linker and a potent topoisomerase I inhibitor. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. The rate of HER2 positivity in biliary tract cancer (BTC) has been reported to be 5-20%, and case reports and clinical trials have suggested that HER2 inhibitors might be active in HER2-positive BTC. Here we describe the rationale and design of the phase II HERB trial that will evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing unresectable or recurrent BTC. The primary end point will be the centrally assessed objective response rate in HER2-positive patients.


Trastuzumab deruxtecan (DS-8201) is a new drug against HER2, a receptor on cell membranes that has sensitivity to targeted inhibitors. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. Some studies have suggested that HER2 inhibitors might be active in HER2-positive biliary tract cancers. This article describes the design of a new clinical trial. The HERB trial is designed to evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing biliary tract cancers. Clinical trial registration: JMA-IIA00423.


Assuntos
Neoplasias da Mama , Imunoconjugados , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2 , Trastuzumab/efeitos adversos
15.
PLoS One ; 17(5): e0267027, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35503762

RESUMO

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.


Assuntos
Neoplasias da Mama , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/uso terapêutico , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Trastuzumab/genética , Trastuzumab/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
16.
Drugs Today (Barc) ; 58(5): 213-222, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35535813

RESUMO

Cervical cancer is one of the most common gynecological malignancies. At present, cytotoxic chemotherapeutic drugs and immunotherapy are the main therapeutic options for recurrent and metastatic cervical cancer. Tisotumab vedotin is an antibody-drug conjugate (ADC) and a potential novel treatment for cervical carcinoma. Tisotumab vedotin targets tissue factor (TF), which is highly expressed on the surface of cervical cancer cells, by delivering the cytotoxic agent monomethyl auristatin E (MMAE) directly into tumor cells. Currently, the U.S. Food and Drug Administration (FDA) has approved tisotumab vedotin for the treatment of adult female patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This article reviews the results of preclinical studies and clinical trials of tisotumab vedotin. The findings suggest that tisotumab vedotin can induce clinically significant and long-lasting remission with controllable and tolerable safety in the difficult-to-treat group of cervical cancer patients.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias do Colo do Útero , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Imunoconjugados/uso terapêutico , Oligopeptídeos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
17.
Anal Chim Acta ; 1213: 339960, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35641064

RESUMO

For real-time and high-sensitivity analysis of low-concentration targets, a sandwich immunoassay using second antibody-second gold nanoparticle (2nd Ab-2nd AuNP) conjugates was combined with fiber-optic localized surface plasmon resonance (FO LSPR). An FO LSPR format was constructed by immobilizing AuNPs on a fiber-optic cross-section for compactness, portability, and ease of handling. In addition, it was combined with a microfluidic system to ensure reproducibility and reliability of measurements. A detection limit of 97.6 fg/mL (148 aM) was obtained for thyroglobulin (Tg) without a sandwich assay. The detection limit was enhanced by approximately 15 times (6.6 fg/mL, 10 aM) when a sandwich strategy was performed with a 2nd Ab-2nd AuNP signal amplifier to further improve the responsivity. Additionally, the good selectivity of the proposed method was confirmed against the unpaired antigen. To evaluate its practical applicability in the field, an FO LSPR biosensor boosted with a sandwich assay using antibody-functionalized AuNPs was applied to detect Tg contained in patient serum, and the results were compared and verified with those of a commercial radioimmunoassay kit. Based on the above results, the signal-enhancing immunoassay with FO LSPR will contribute to the development of optical biosensors for early diagnosis and preventive applications.


Assuntos
Técnicas Biossensoriais , Imunoconjugados , Nanopartículas Metálicas , Técnicas Biossensoriais/métodos , Ouro , Humanos , Reprodutibilidade dos Testes , Ressonância de Plasmônio de Superfície/métodos
18.
AAPS J ; 24(4): 70, 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35624189

RESUMO

The main objective of this work was to demonstrate which kind of payload is the suitable choice for antibody-drug conjugates directed to widely expressed tumor-associated antigen. Trop-2 is overexpressed in various solid tumors, but it is also present on the epithelium of several normal tissues. A well-designed anti-Trop-2 ADC demands a good balance of efficacy and toxicity. In this research, MMAE, SN-38, and DXd were selected as candidates for payloads of the anti-Trop-2 mAb SY02. The antitumor activities and safety profiles of these ADCs were investigated to compare the therapeutic windows. Robust in vitro cytotoxicity was observed on human pancreatic cancer cell CFPAC-1 and breast cancer cell MDA-MB-468 with IC50 generally in the subnanomolar range. Consistent with in vitro assay, SY02-DXd and SY02-SN-38 demonstrated superior efficacy in CFPAC-1 xenograft models with TGI rates of 98.2% and 87.3%, respectively. However, SY02-MMAE could hardly inhibit the tumor growth. Subsequently, antitumor activities of these ADCs were further compared in MDA-MB-468 xenograft model. Complete tumor regression was observed in SY02-DXd and SY02-MMAE groups, indicating their potent antitumor activities. In an exploratory safety and pharmacokinetic study, SY02-DXd demonstrated the best safety profile with minimal adverse events in cynomolgus monkeys, while SY02-MMAE exhibited severe on-target skin toxicity which caused death. In conclusion, SY02-DXd demonstrated superior efficacy and safety with the widest therapeutic window. Based on the efficacy and safety results, moderate cytotoxic payloads would be ideal choices for ADCs targeting ubiquitously expressed antigens.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias Pancreáticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Irinotecano , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Sci Rep ; 12(1): 7677, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538109

RESUMO

Antibody-Drug Conjugates (ADCs) have rapidly expanded in the clinic, with 7 new approvals in 3 years. For solid tumors, high doses of ADCs improve tissue penetration and efficacy. These doses are enabled by lower drug-to-antibody ratios and/or co-administration of unconjugated antibody carrier doses to avoid payload toxicity. While effective for highly expressed targets, these strategies may not maintain efficacy with lower target expression. To address this issue, a carrier dose that adjusts binding in situ according to cellular expression was designed using computational modeling. Previous studies demonstrated that coadministration of unconjugated antibody with the corresponding ADC at an 8:1 ratio improves ADCs efficacy in high HER2 expressing tumors. By designing a High Avidity, Low Affinity (HALA) carrier antibody, ADC binding is partially blocked in high expression cells, improving tissue penetration. In contrast, the HALA antibody cannot compete with the ADC in low expressing cells, allowing ADC binding to the majority of receptors. Thus, the amount of competition from the carrier dose automatically adjusts to expression levels, allowing tailored competition between different patients/metastases. The computational model highlights two dimensionless numbers, the Thiele modulus and a newly defined competition number, to design an optimal HALA antibody carrier dose for any target.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Anticorpos , Linhagem Celular Tumoral , Humanos , Imunoconjugados/farmacologia
20.
Drug Deliv ; 29(1): 1335-1344, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35506447

RESUMO

Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.


Assuntos
Antineoplásicos , Neoplasias da Mama , Imunoconjugados , Neoplasias Gástricas , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico
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