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1.
Bioconjug Chem ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32667786

RESUMO

Several antibody-drug conjugates (ADCs) have failed to achieve a sufficiently large therapeutic window in patients due to toxicity induced by unspecific payload release in the circulation or ADC uptake into healthy organs. Herein, we describe the successful engineering of ADCs consisting of novel linkers, which are efficiently and selectively cleaved by the tumor-associated protease legumain. ADCs generated via this approach demonstrate high potency and a preferential activation in tumors compared to healthy tissue, thus providing an additional level of safety. A remarkable tolerance of legumain for different linker peptides, including those with just a single asparagine residue, together with a modifier of the physicochemical metabolite profile, proves the broad applicability of this approach for a tailored design of ADCs.

2.
J Org Chem ; 85(3): 1446-1457, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31813224

RESUMO

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

3.
Chemistry ; 25(35): 8208-8213, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-30869180

RESUMO

Many antibody-drug conjugates (ADCs) have failed to achieve a sufficient therapeutic window in clinical studies either due to target-mediated or off-target toxicities. To achieve an additional safety level, a new class of antibody-prodrug conjugates (APDCs) directed against different targets in solid tumors is here described. The tumor-associated lysosomal endopeptidase legumain with a unique cleavage sequence was utilized for APDC metabolism. Legumain-activatable APDCs were as potent as their cathepsin B-activatable analogues. The peptide sequence susceptible to legumain cleavage was optimized for further discrimination of the formation of active metabolites within tumor cells versus healthy tissues, leveraging different tissue-specific legumain activities. Optimized APDCs with slow legumain-mediated conversion reduced preclinically the levels of active metabolite in healthy organs while retaining high activity against different TWEAKR- and B7H3-expressing tumors.


Assuntos
Anticorpos/química , Antineoplásicos/química , Cisteína Endopeptidases/metabolismo , Imunoconjugados/química , Cinesina/antagonistas & inibidores , Oligopeptídeos/química , Pró-Fármacos/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Antígenos B7/genética , Antígenos B7/imunologia , Antígenos B7/metabolismo , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/metabolismo , Camundongos
4.
Chemistry ; 25(7): 1696-1700, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452790

RESUMO

This work takes advantage of one of the hallmarks of cancer, that is, the presence of tumor infiltrating cells of the immune system and leukocyte-secreted enzymes, to promote the activation of an anticancer drug at the tumor site. The peptidomimetic integrin ligand cyclo(DKP-RGD) was found to accumulate on the surface of αv ß3 integrin-expressing human renal cell carcinoma 786-O cells. The ligand was conjugated to the anticancer drug paclitaxel through a Asn-Pro-Val (NPV) tripeptide linker, which is a substrate of neutrophil-secreted elastase. In vitro linker cleavage assays and cell antiproliferative experiments demonstrate the efficacy of this tumor-targeting conjugate, opening the way to potential therapeutic applications.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Integrina alfaVbeta3/metabolismo , Elastase de Leucócito/metabolismo , Paclitaxel/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Integrina alfaVbeta3/genética , Ligantes , Microscopia Confocal , Oligopeptídeos/química , Paclitaxel/química , Paclitaxel/farmacologia , Vitronectina/química , Vitronectina/metabolismo
5.
Angew Chem Int Ed Engl ; 57(46): 15243-15247, 2018 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-30180286

RESUMO

The number of cytotoxic payload classes successfully employed in antibody-drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) as a novel payload class providing highly potent ADCs against different targets, for instance HER-2 or TWEAKR/Fn14. Aspects of technical optimization include the development of different linker attachment sites, the stabilization of ADC linkage to avoid payload deconjugation and finally, the tailor-made design of active metabolites with a long lasting intracellular exposure in the tumor matching the mode of action of KSP inhibition. These KSPi-ADCs are highly potent and selective in vitro and demonstrate in vivo efficacy in a broad panel of tumor models including complete regressions in a patient-derived urothelial cancer model.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Imunoconjugados/química , Imunoconjugados/farmacologia , Cinesina/antagonistas & inibidores , Pirróis/química , Pirróis/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Pirróis/uso terapêutico
6.
ChemMedChem ; 12(10): 728-737, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28488817

RESUMO

Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Dipeptídeos/farmacologia , Cardiopatias/tratamento farmacológico , Pró-Fármacos/farmacologia , Piridinas/farmacologia , Receptor A1 de Adenosina/metabolismo , Agonistas do Receptor A1 de Adenosina/administração & dosagem , Agonistas do Receptor A1 de Adenosina/química , Administração Oral , Animais , Doença Crônica , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Injeções Intravenosas , Estrutura Molecular , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Piridinas/administração & dosagem , Piridinas/química , Ratos , Solubilidade , Relação Estrutura-Atividade
7.
Mol Cancer Ther ; 16(5): 893-904, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28292941

RESUMO

C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non-small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody-drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893-904. ©2017 AACR.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Moléculas de Adesão Celular/imunologia , Imunoconjugados/administração & dosagem , Aminobenzoatos/química , Aminobenzoatos/imunologia , Animais , Anticorpos Monoclonais/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Moléculas de Adesão Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/imunologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Camundongos , Oligopeptídeos/química , Oligopeptídeos/imunologia , Paclitaxel/administração & dosagem , Paclitaxel/imunologia , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vimblastina/imunologia , Vinorelbina , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Res ; 76(21): 6331-6339, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27543601

RESUMO

The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331-9. ©2016 AACR.


Assuntos
Aminobenzoatos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/análise , Animais , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Beilstein J Org Chem ; 8: 1652-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23209498

RESUMO

Thio-Ugi reactions are described as an excellent synthetic tool for the synthesis of sterically highly hindered endothiopeptides. S-Methylation and subsequent amidine formation can be carried out in an inter- as well as in an intramolecular fashion. The intramolecular approach allows the synthesis of the bottromycin ring system in a straightforward manner.

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