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1.
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
2.
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
3.
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
4.
Molecules ; 27(12)2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35744930

RESUMO

Compromised activity is a common impediment for biologics requiring endosome trafficking into target cells. In cancer cells, antibody-drug conjugates (ADCs) are trapped in endosomes or subsequently pumped extracellularly, leading to a reduction in intracellular accumulation. In subsets of dendritic cells (DCs), endosome-engulfed antigens face non-specific proteolysis and collateral damage to epitope immunogenicity before proteasomal processing and subsequent surface presentation. To bypass these shortcomings, we devised Accum™, a conjugable biotechnology harboring cholic acid (ChAc) and a nuclear localization signal (NLS) sequence for endosome escape and prompt nuclear targeting. Combined, these mechanisms culminate in enhanced intracellular accumulation and functionalization of coupled biologics. As proof-of-principle, we have biochemically characterized Accum, demonstrating its adaptability to ADCs or antigens in different cancer settings. Additionally, we have validated that endosome escape and nuclear routing are indispensable for effective intracellular accumulation and guaranteed target cell selectivity. Importantly, we have demonstrated that the unique mechanism of action of Accum translates into enhanced tumor cytotoxicity when coupled to ADCs, and durable therapeutic and prophylactic anti-cancer immunogenicity when coupled to tumor antigens. As more pre-clinical evidence accumulates, the adaptability, unique mechanism of action, and high therapeutic potency of Accum signal a promising transition into clinical investigations in the context of onco-immunotherapy.


Assuntos
Produtos Biológicos , Imunoconjugados , Antígenos de Neoplasias , Produtos Biológicos/farmacologia , Endossomos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoterapia , Sinais de Localização Nuclear/química
5.
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
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.
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
8.
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
9.
J Med Chem ; 65(10): 7141-7153, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35522590

RESUMO

By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity in vitro with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition in vivo under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.


Assuntos
Neoplasias da Mama , Imunoconjugados , Maitansina , Neoplasias Pancreáticas , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Feminino , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Maitansina/farmacologia , Maitansina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Receptor ErbB-2 , Trastuzumab
10.
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
11.
Biomed Pharmacother ; 151: 113090, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35567988

RESUMO

The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of 89Zr-labeled chDAB4. Similarly, no differences were observed between LL2 tumor-bearing wild-type and Fcγ KO mice in post-chemotherapy uptake of 89Zr-chDAB4. Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous 'eat me' signals rather than depend on functional FcγR expression for phagocytosis.


Assuntos
Imunoconjugados , Neoplasias , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Camundongos , Receptores de IgG/genética , Receptores de IgG/metabolismo , Distribuição Tecidual
12.
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
13.
Sci Rep ; 12(1): 7262, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508689

RESUMO

Next-generation site-specific cysteine-based antibody-drug-conjugates (ADCs) broaden therapeutic index by precise drug-antibody attachments. However, manufacturing such ADCs for clinical validation requires complex full reduction and reoxidation processes, impacting product quality. To overcome this technical challenge, we developed a novel antibody manufacturing process through cysteine (Cys) metabolic engineering in Chinese hamster ovary cells implementing a unique cysteine-capping technology. This development enabled a direct conjugation of drugs after chemoselective-reduction with mild reductant tris(3-sulfonatophenyl)phosphine. This innovative platform produces clinical ADC products with superior quality through a simplified manufacturing process. This technology also has the potential to integrate Cys-based site-specific conjugation with other site-specific conjugation methodologies to develop multi-drug ADCs and exploit multi-mechanisms of action for effective cancer treatments.


Assuntos
Antineoplásicos , Imunoconjugados , Animais , Anticorpos , Antineoplásicos/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Cisteína , Dissulfetos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Engenharia Metabólica
14.
Drug Deliv ; 29(1): 1243-1256, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35416106

RESUMO

The present study aimed to evaluate the anti-tumor efficacy of the epidermal growth factor receptor (EGFR)-targeting recombinant fusion protein Fv-LDP-D3 and its antibody-drug conjugate Fv-LDP-D3-AE against esophageal cancer. Fv-LDP-D3, consisting of the fragment variable (Fv) of an anti-EGFR antibody, the apoprotein of lidamycin (LDP), and the third domain of human serum albumin (D3), exhibited a high binding affinity for EGFR-overexpressing esophageal cancer cells, inhibited EGFR phosphorylation and down-regulated inosine monophosphate dehydrogenase type II (IMPDH2) expression. Fv-LDP-D3 was taken up by cancer cells through intensive macropinocytosis; it inhibited the proliferation and induced the apoptosis of esophageal cancer cells. In vivo imaging revealed that Fv-LDP-D3 displayed specific tumor-site accumulation and a long-lasting retention over a 26-day period. Furthermore, Fv-LDP-D3-AE, a pertinent antibody-drug conjugate prepared by integrating the enediyne chromophore of lidamycin into the Fv-LDP-D3 molecule, displayed highly potent cytotoxicity, inhibited migration and invasion, induced apoptosis and DNA damage, arrested cells at G2/M phase, and caused mitochondrial damage in esophageal cancer cells. More importantly, both of Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the growth of esophageal cancer xenografts in athymic mice at well tolerated doses. The present results indicate that Fv-LDP-D3, and Fv-LDP-D3-AE exert prominent antitumor efficacy associated with targeting EGFR, suggesting their potential as promising candidates for targeted therapy against esophageal cancer.


Assuntos
Neoplasias Esofágicas , Imunoconjugados , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Enedi-Inos/química , Enedi-Inos/farmacologia , Receptores ErbB/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Humanos , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , IMP Desidrogenase/uso terapêutico , Imunoconjugados/metabolismo , Imunoconjugados/farmacologia , Camundongos , Camundongos Nus , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Pharm ; 19(5): 1422-1433, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35389227

RESUMO

With a wide range of available cytotoxic therapeutics, the main focus of current cancer research is to deliver them specifically to the cancer cells, minimizing toxicity against healthy tissues. Targeted therapy utilizes different carriers for cytotoxic drugs, combining a targeting molecule, typically an antibody, and a highly toxic payload. For the effective delivery of such cytotoxic conjugates, a molecular target on the cancer cell is required. Various proteins are exclusively or abundantly expressed in cancer cells, making them a possible target for drug carriers. Fibroblast growth factor receptor 1 (FGFR1) overexpression has been reported in different types of cancer, but no FGFR1-targeting cytotoxic conjugate has been approved for therapy so far. In this study, the FGFR1-targeting peptide previously described in the literature was reformatted into a peptibody-peptide fusion with the fragment crystallizable (Fc) domain of IgG1. PeptibodyC19 can be effectively internalized into FGFR1-overexpressing cells and does not induce cells' proliferation. The main challenge for its use as a cytotoxic conjugate is a cysteine residue located within the targeting peptide. A standard drug-conjugation strategy based on the maleimide-thiol reaction involves modification of cysteines within the Fc domain hinge region. Applied here, however, may easily result in the modification of the targeting peptide with the drug, limiting its affinity to the target and therefore the potential for specific drug delivery. To investigate if this is the case, we have performed conjugation reactions with different auristatin derivatives (PEGylated and unmodified) under various conditions. By controlling the reduction conditions and the type of cytotoxic payload, different numbers of cysteines were substituted, allowing us to avoid conjugating the drug to the targeting peptide, which could affect its binding to FGFR1. The optimized protocol with PEGylated auristatin yielded doubly substituted peptibodyC19, showing specific cytotoxicity toward the FGFR1-expressing lung cancer cells, with no effect on cells with low FGFR1 levels. Indeed, additional cysteine poses a risk of unwanted modification, but changes in the type of cytotoxic payload and reaction conditions allow the use of standard thiol-maleimide-based conjugation to achieve standard Fc hinge region cysteine modification, analogously to antibody-drug conjugates.


Assuntos
Antineoplásicos , Imunoconjugados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisteína/química , Imunoconjugados/química , Imunoconjugados/farmacologia , Maleimidas/química , Polietilenoglicóis , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Compostos de Sulfidrila
16.
Biochim Biophys Acta Gen Subj ; 1866(7): 130155, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35469978

RESUMO

BACKGROUND: Site-specific coupling of toxin entities to antibodies has become a popular method of synthesis of antibody-drug conjugates (ADCs), as it leads to a homogenous product and allows a free choice of a convenient site for conjugation. METHODS: We introduced a short motif, containing a single cysteine surrounded by aromatic residues, into the N-terminal FG-loop of the CH2 domain of two model antibodies, cetuximab and trastuzumab. The extent of conjugation with toxic payload was examined with hydrophobic interaction chromatography and mass spectrometry and the activity of resulting conjugates was tested on antigen-overexpressing cell lines. RESULTS: Antibody mutants were amenable for rapid coupling with maleimide-based linker endowed toxin payload and the modifications did not impair their reactivity with target cell lines or negatively impact their biophysical properties. Without any previous reduction, up to 50% of the antibody preparation was found to be coupled with two toxins per molecule. After the isolation of this fraction with preparative hydrophobic interaction chromatography, the ADC could elicit a potent cytotoxic effect on the target cell lines. CONCLUSION: By fine-tuning the microenvironment of the reactive cysteine residue, this strategy offers a simplified protocol for production of site-selectively coupled ADCs. GENERAL SIGNIFICANCE: Our unique approach allows the generation of therapeutic ADCs with controlled chemical composition, which facilitates the optimization of their pharmacological activity. This strategy for directional coupling could in the future simplify the construction of ADCs with double payloads ("dual warheads") introduced with orthogonal techniques.


Assuntos
Antineoplásicos , Imunoconjugados , Antineoplásicos/farmacologia , Cisteína/química , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Espectrometria de Massas , Trastuzumab/farmacologia
17.
Int J Mol Sci ; 23(6)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-35328459

RESUMO

Therapeutic antibodies used to treat cancer are effective in patients with advanced-stage disease. For example, antibodies that activate T-lymphocytes improve survival in many cancer subtypes. In addition, antibody-drug conjugates effectively target cytotoxic agents that are specific to cancer. This review discusses radiation-inducible antigens, which are stress-regulated proteins that are over-expressed in cancer. These inducible cell surface proteins become accessible to antibody binding during the cellular response to genotoxic stress. The lead antigens are induced in all histologic subtypes and nearly all advanced-stage cancers, but show little to no expression in normal tissues. Inducible antigens are exploited by using therapeutic antibodies that bind specifically to these stress-regulated proteins. Antibodies that bind to the inducible antigens GRP78 and TIP1 enhance the efficacy of radiotherapy in preclinical cancer models. The conjugation of cytotoxic drugs to the antibodies further improves cancer response. This review focuses on the use of radiotherapy to control the cancer-specific binding of therapeutic antibodies and antibody-drug conjugates.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/radioterapia
18.
Cells ; 11(5)2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35269424

RESUMO

Significant progress has been achieved over the last decades in understanding the biology and mechanisms of tumor progression in urothelial carcinoma (UC). Although the therapeutic landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors, advanced UC is still associated with rapidly progressing disease and poor survival. The increasing knowledge of the pathogenesis and molecular pathways underlying cancer development and progression is leading the introduction of target therapies, such as the recently approved FGFR inhibitor Erdafitinib, or the anti-nectin 4 antibody drug-conjugate Enfortumab vedotin. Antibody drug conjugates represent an innovative therapeutic approach that allows the combination of a tar get-specific monoclonal antibody covalently conjugated via a linker to a cytotoxic agent (payload). UC is a perfect candidate for this therapeutic approach since it is particularly enriched in antigen expression on its surface and each specific antigen can represent a potential therapeutic target. In this review we summarize the mechanism of action of ADCs, their applications in localized and metastatic UC, the main mechanisms of resistance, and future perspectives for their use in clinical practice.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Imunoconjugados , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico
19.
Zhongguo Fei Ai Za Zhi ; 25(3): 214-218, 2022 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-35340165

RESUMO

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world. Non-small cell lung cancer (NSCLC) is one of the most important pathological types of lung cancer. The prognosis of advanced NSCLC is poor and medical treatment is still the main treatment option. Antibody-drug conjugates (ADCs) are the kind of potentially new anti-tumor drugs, consisting of monoclonal antibodies conjugated to the cytotoxic payloads via the synthetic linkers. They have a broad application prospect in solid tumors such as lung cancer. This article focuses on the mechanism of action and research progress of ADCs in advanced NSCLC.
.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico
20.
J Med Chem ; 65(6): 4496-4499, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35285623

RESUMO

The application of antibody-drug conjugates (ADCs) to fields outside of oncology is increasing but is still relatively uncommon. A recent publication describes the conjugation of glucocorticoid receptor modulators to antibodies as a means of improving the separation between desired anti-inflammatory activity and unwanted systemic side effects.


Assuntos
Imunoconjugados , Anticorpos Monoclonais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico
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