RESUMEN
Antibody-drug conjugates (ADC) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The activity and safety profile of an ADC depends on its construction: antibody, payload, linker, and conjugation method, as well as the number of payload drugs per antibody [drug-to-antibody ratio (DAR)]. To allow for ADC optimization for a given target antigen, we developed Dolasynthen (DS), a novel ADC platform based on the payload auristatin hydroxypropylamide, that enables precise DAR-ranging and site-specific conjugation. We used the new platform to optimize an ADC that targets B7-H4 (VTCN1), an immune-suppressive protein that is overexpressed in breast, ovarian, and endometrial cancers. XMT-1660 is a site-specific DS DAR 6 ADC that induced complete tumor regressions in xenograft models of breast and ovarian cancer as well as in a syngeneic breast cancer model that is refractory to PD-1 immune checkpoint inhibition. In a panel of 28 breast cancer PDXs, XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a phase I study (NCT05377996) in patients with cancer.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Inmunoconjugados , Humanos , Femenino , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Anticuerpos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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/farmacologíaRESUMEN
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/farmacologíaRESUMEN
Novel tricyclic imidazoline antagonists of the adenosine A1 receptor are described. For key compounds, the selectivity level over other adenosine receptor subtypes is examined along with their in vivo effects in a rat diuresis model. Compound 14, the (R)-isomer of 7,8-dihydro-8-ethyl-2-(4-bicyclo[2.2.2]octan-1-ol)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one, is a particularly potent adenosine A1 receptor antagonist with good selectivity over the other three adenosine receptor subtypes: A1 (human) Ki=22 nM; A2A (human) Ki=4400 nM; A2B (human) Ki=580 nM; A3 (human) Ki>or=10,000 nM. Imidazoline 14 is a competitive adenosine A1 receptor antagonist with a pA2 value of 8.88 and is highly soluble in water (>100 mg/mL). In addition, it has an oral bioavailability of 84% and an oral half-life of 3.8 h in rats. When orally administered in a rat diuresis model, compound 14 promoted sodium excretion (ED50=0.01 mg/kg). This level of efficacy is comparable to that of BG9928, a selective adenosine A1 receptor antagonist that is currently in clinical trials as a treatment for congestive heart failure. Additional modifications to 14 also showed that the bridgehead hydroxyl group could be replaced with a propionic acid (compound 36) without a significant loss in binding affinity or in vivo activity.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Imidazolinas/síntesis química , Purinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Semivida , Atrios Cardíacos/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Imidazolinas/farmacocinética , Imidazolinas/farmacología , Técnicas In Vitro , Natriuresis/efectos de los fármacos , Purinas/farmacocinética , Purinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Adenosina A2/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In the search for a selective adenosine A1 receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4-substituted 8-cyclohexyl and 8-bicyclo[2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A1, A2A, A2B, and A3 receptors are presented. Bicyclo[2.2.2]octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/kg po). Optimization of the bridgehead substituent led to propionic acid 29 (BG9928), which retained high potency (hA1, Ki=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Xantinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Cricetinae , Cricetulus , Diuresis/efectos de los fármacos , Perros , Atrios Cardíacos/efectos de los fármacos , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Xantinas/farmacocinética , Xantinas/farmacologíaRESUMEN
During the search for second-generation adenosine A(1) receptor antagonist alternatives to the clinical candidate 8-(3-oxa-tricyclo[3.2.1.0(2,4)]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (BG9719), we developed a series of novel xanthines substituted with norbornyl-lactones that possessed high binding affinities for adenosine A(1) receptors and in vivo activity.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Compuestos Bicíclicos con Puentes/química , Lactonas/química , Norbornanos/farmacología , Xantinas/farmacología , Antagonistas del Receptor de Adenosina A2 , Antagonistas del Receptor de Adenosina A3 , Animales , Unión Competitiva/efectos de los fármacos , Línea Celular , Humanos , Ligandos , Estructura Molecular , Norbornanos/síntesis química , Norbornanos/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Xantinas/síntesis química , Xantinas/químicaRESUMEN
A novel [1,2,4]triazolo[1,5-a]pyrazine core was synthesized and coupled with terminal acetylenes. The structure-activity relationship of the alkynes from this novel template was studied for their in vitro and in vivo adenosine A(2A) receptor antagonism. Selected compounds from this series were shown to have potent in vitro and in vivo activities against adenosine A(2A) receptor. Compound 12, in particular, was found to be orally active at 3mg/kg in both a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model.