RESUMEN

Although the recent FDA approval of six new antibody-drug conjugates (ADCs) is promising, attrition of ADCs during clinical development remains high. The inherent complexity of ADCs is a double-edged sword that provides opportunities for perfecting therapeutic action while also increasing confounding factors in therapeutic failures. ADC design drives their pharmacokinetics and pharmacodynamics, and requires deeper analysis than the commonly used Cmax and area under the curve (AUC) metrics to scale dosing to the clinic. Common features of current FDA-approved ADCs targeting solid tumors include humanized IgG1 antibody domains, highly expressed tumor receptors, and large antibody doses. The potential consequences of these shared features for clinical pharmacokinetics and mechanism of action are discussed, and key design aspects for successful solid tumor ADCs are highlighted.

Asunto(s)

Inmunoconjugados , Neoplasias , Benchmarking , Humanos , Neoplasias/tratamiento farmacológico

RESUMEN

Ewing sarcoma is a bone and soft tissue tumor predominantly affecting adolescents and young adults. To characterize changes in anticancer drug activity and intratumor drug distribution during the evolution of Ewing sarcomas, we used immunodeficient mice to establish pairs of patient-derived xenografts (PDX) at early (initial diagnosis) and late (relapse or refractory progression) stages of the disease from three patients. Analysis of copy number alterations (CNA) in early passage PDX tissues showed that two tumor pairs established from patients which responded initially to therapy and relapsed more than one year later displayed similar CNAs at early and late stages. For these two patients, PDX established from late tumors were more resistant to chemotherapy (irinotecan) than early counterparts. In contrast, the tumor pair established at refractory progression showed highly dissimilar CNA profiles, and the pattern of response to chemotherapy was discordant with those of relapsed cases. In mice receiving irinotecan infusions, the level of SN-38 (active metabolite of irinotecan) in the intracellular tumor compartment was reduced in tumors at later stages compared to earlier tumors for those pairs bearing similar CNAs, suggesting that distribution of anticancer drug shifted toward the extracellular compartment during clonal tumor evolution. Overexpression of the drug transporter P-glycoprotein in late tumor was likely responsible for this shift in drug distribution in one of the cases.

Asunto(s)

Antineoplásicos , Neoplasias Óseas , Preparaciones Farmacéuticas , Sarcoma de Ewing , Adolescente , Animales , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Humanos , Irinotecán , Ratones , Sarcoma de Ewing/tratamiento farmacológico

RESUMEN

Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts. We showed that the extent of tumor penetration by SN-38 was significantly higher in mice receiving the targeted nano-drug delivery system when compared to non-targeted system or free drug. This selective penetration of the tumor extracellular fluid translated into a strong anti-tumor effect prolonging survival of mice bearing GD2-high neuroblastomas in vivo.

Asunto(s)

Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Líquido Extracelular/metabolismo , Inmunoglobulina G/administración & dosificación , N-Acetilgalactosaminiltransferasas/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Neuroblastoma/metabolismo , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales de Origen Murino , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/química , Camptotecina/farmacocinética , Línea Celular Tumoral , Preescolar , Liberación de Fármacos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoglobulina G/química , Irinotecán , Masculino , Ratones Desnudos , N-Acetilgalactosaminiltransferasas/genética , N-Acetilgalactosaminiltransferasas/inmunología , N-Acetilgalactosaminiltransferasas/metabolismo , Nanopartículas/química , Neuroblastoma/tratamiento farmacológico , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

We report the use of optical imaging strategies to noninvasively examine photosensitizer distribution and physiological and host responses to 2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) of EMT6 tumors established in the ears of BALB/c mice. 24 h following intravenous (IV) administration of 1 µmol kg(-1) HPPH, wide-field fluorescence imaging reveals tumor selectivity with an approximately 2-3-fold differential between tumor and adjacent normal tissue. Confocal microscopy demonstrates a relatively homogeneous intratumor HPPH distribution. Labeling of host cells using fluorophore-conjugated antibodies allowed the visualization of Gr1(+)/CD11b(+) leukocytes and major histocompatibility complex class II (MHC-II)(+) cells in vivo. Imaging of the treated site at different time-points following irradiation shows significant and rapid increases in Gr1(+) cells in response to therapy. The maximum accumulation of Gr1(+) cells is found at 24 h post-irradiation, followed by a decrease at the 48 h time-point. Using IV-injected FITC-conjugated dextran as a fluorescent perfusion marker, we imaged tissue perfusion at different times post-irradiation and found that the reduced Gr1(+ )cell density at 48 h correlated strongly with functional damage to the vasculature as reported via decreased perfusion status. Dual color confocal imaging experiments demonstrates that about 90% of the anti-Gr1 cell population co-localized with anti-CD11b labeling, thus indicating that majority of the Gr1-labeled cells were neutrophils. At 24 h post-PDT, an approximately 2-fold increase in MHC-II+ cells relative to untreated control is also observed. Co-localization analysis reveals an increase in the fraction of Gr1(+) cells expressing MHC-II, suggesting that HPPH-PDT is stimulating neutrophils to express an antigen-presenting phenotype.