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1.
Bioorg Med Chem Lett ; 72: 128876, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-35788036

RESUMEN

Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10-11-10-8 M) against a variety of HER2-expressing cancer cell lines. Several peptide-linked variants of the lead compound were prepared and conjugated to trastuzumab to afford ADCs with drug-to-antibody (DAR) ratios ranging from 3 to 5. The ADCs exhibited antigen-dependent cytotoxicity in vitro and potently suppressed tumor xenograft growth in vivo in a target-dependent manner. Moreover, the ADCs were well-tolerated in both mouse and rat. This work demonstrates for the first time that PBD polyamide hybrids can serve as effective ADC payloads.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Animales , Antineoplásicos/farmacología , Benzodiazepinas , Línea Celular Tumoral , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Nylons/farmacología , Pirroles , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Mol Cancer Ther ; 23(4): 541-551, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38354416

RESUMEN

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Neoplasias , Humanos , Ratas , Animales , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Alquilantes , Neoplasias/tratamiento farmacológico , ADN/metabolismo , Línea Celular Tumoral , Antineoplásicos/farmacología
3.
Mol Cancer Ther ; 20(5): 885-895, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33722857

RESUMEN

After significant effort over the last 30 years, antibody-drug conjugates (ADC) have recently gained momentum as a therapeutic modality, and nine ADCs have been approved by the FDA to date, with additional ADCs in late stages of development. Here, we introduce dolaflexin, a novel ADC technology that overcomes key limitations of the most common ADC platforms with two key features: a higher drug-to-antibody ratio and a novel auristatin with a controlled bystander effect. The novel, cell permeable payload, auristatin F-hydroxypropylamide, undergoes metabolic conversion to the highly potent, but less cell permeable auristatin F to balance the bystander effect through drug trapping within target cells. We conducted studies in mice, rats, and cynomolgus monkeys to complement in vitro characterization and contrasted the performance of dolaflexin with regard to antitumor activity, pharmacokinetic properties, and safety in comparison with the ADC platform utilized in the approved ADC ado-trastuzumab emtansine (T-DM1). A HER2-targeted dolaflexin ADC was shown to have a much lower threshold of antigen expression for potent cell killing in vitro, was effective in vivo in tumors with low HER2 expression, and induced tumor regressions in a xenograft model that is resistant to T-DM1.


Asunto(s)
Inmunoconjugados/uso terapéutico , Oligopéptidos/uso terapéutico , Polímeros/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Inmunoconjugados/farmacología , Ratones , Ratones SCID , Oligopéptidos/farmacología , Polímeros/farmacología
4.
Mol Cancer Ther ; 20(5): 896-905, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33722858

RESUMEN

Target selection for antibody-drug conjugates (ADC) frequently focuses on identifying antigens with differential expression in tumor and normal tissue, to mitigate the risk of on-target toxicity. However, this strategy restricts the possible target space. SLC34A2/NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors including lung and ovarian carcinoma, as well as the normal tissues from which these tumors arise. Previous clinical trials with a NaPi2b targeting MMAE-ADCs have shown objective durable responses. However, the protein-based biomarker assay developed for use in that study was unable to discern a statistically significant relationship between NaPi2b protein expression and the probability of response. XMT-1536 is a NaPi2b targeting ADC comprised of a unique humanized antibody conjugated with 10-15 auristatin F- hydroxypropylamide (AF-HPA) payload molecules via the Dolaflexin platform. AF-HPA is a cell-permeable, antimitotic compound that is slowly metabolized intratumorally to an active, very low-permeable metabolite, auristatin F (AF), resulting in controlled bystander killing. We describe the preclinical in vitro and in vivo antitumor effects of XMT-1536 in models of ovarian and lung adenocarcinoma. Pharmacokinetic analysis showed approximately proportional increases in exposure in rat and monkey. Systemic free AF-HPA and AF concentrations were observed to be low in all animal species. Finally, we describe a unique IHC reagent, generated from a chimeric construct of the therapeutic antibody, that was used to derive a target expression and efficacy relationship in a series of ovarian primary xenograft cancer models.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Inmunoconjugados/uso terapéutico , Neoplasias/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Polímeros/uso terapéutico , Animales , Femenino , Humanos , Inmunoconjugados/farmacología , Ratones , Ratones SCID , Oligopéptidos/farmacología , Polímeros/farmacología
5.
Ann N Y Acad Sci ; 959: 434-47, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11976216

RESUMEN

It has been proposed that age-dependent accumulation of somatic mutations in mtDNA is responsible for some aspects of the aging process. However, most cells contain hundreds to thousands of mtDNA molecules. Any nascent somatic mutant therefore appears as a single copy among a majority of wild-type species. A single mutant molecule is unlikely to influence the physiology of the cell and thus cannot play a role in the aging process. To affect cellular physiology, the nascent somatic mutants must somehow accumulate clonally in the cell to significant levels. The evidence supporting the view that, indeed, clonal expansion of mtDNA mutations is a widespread process in various human tissues, and the mechanisms by which clonal expansions may affect the aging process, are reviewed. Originally, clonal expansion was demonstrated for mtDNA with large deletions in muscle. Cell-by-cell analysis of human cardiomyocytes and buccal epithelial cells revealed that clonal expansion affects point mtDNA mutations as well as deletions. Expansions are not limited to muscle, but likely are present in most tissues, and almost every cell of an aged tissue is likely to be affected by an expansion. While the very existence of clonal expansion is beyond doubt, the mechanisms driving this process are largely controversial. The hypotheses explaining expansion includes random or various selective mechanisms, or both. We show that the spectra of expanded point mutations are drastically different in cardiomyocytes and epithelial cells. This suggests that the mechanisms of expansion in these tissues are different. In particular, we propose random segregation and positive selection models for epithelial and muscle cells, respectively.


Asunto(s)
Envejecimiento/genética , ADN Mitocondrial/genética , Mucosa Bucal/citología , Mutación Puntual , Envejecimiento/fisiología , Separación Celular , Células Clonales , ADN Mitocondrial/metabolismo , Células Epiteliales/fisiología , Corazón/fisiología , Humanos , Mucosa Bucal/fisiología , Miocardio/citología
6.
Proc Natl Acad Sci U S A ; 99(8): 5521-6, 2002 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-11943860

RESUMEN

Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells. Significant qualitative differences observed between the spectra of clonally expanded mutations in proliferating epithelial cells and postmitotic cardiomyocytes suggest, however, that either the processes generating these mutations or mechanisms driving them to homoplasmy are likely to be fundamentally different between the two tissues. Furthermore, the ability of somatic mtDNA mutations to expand (required for their phenotypic expression), as well as their apparently high incidence, reinforces the possibility that these mutations may be involved actively in various physiological processes such as aging and degenerative disease. The abundance of clonally expanded point mutations in individual cells of normal tissues also suggests that the recently discovered accumulation of mtDNA mutations in tumors may be explained by processes that are similar or identical to those operating in the normal tissue.


Asunto(s)
ADN Mitocondrial/genética , Mutación Puntual , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento , División Celular , Línea Celular , Células Cultivadas , Mejilla , Niño , Preescolar , Células Epiteliales/metabolismo , Eliminación de Gen , Genoma , Humanos , Lactante , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitosis , Mucosa Bucal/citología , Mutación , Miocardio/citología , Neoplasias/genética , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Distribución Tisular
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