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1.
Drug Metab Dispos ; 44(5): 617-23, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26669328

RESUMEN

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Inmunoconjugados/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Industria Farmacéutica/métodos , Humanos
2.
Regul Toxicol Pharmacol ; 73(2): 562-70, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26382609

RESUMEN

Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined. Bococizumab was well tolerated and there were no effects on ovarian or uterine parameters. Maternal and fetal bococizumab exposure increased with increasing dose, with a corresponding dose-dependent decrease in fetal cholesterol levels. Maternal cholesterol levels were decreased significantly, with reductions that were of a similar magnitude regardless of dose. In the definitive embryo-fetal development study bococizumab was administered to pregnant SD rats (n = 20/group) at 0, 10, 30, and 100 mg/kg and no adverse maternal or developmental effects were observed up to 100 mg/kg. These studies have provided an appropriate and relevant safety assessment of bococizumab in pregnant rats to inform human risk assessment, demonstrating no adverse effects on embryo-fetal development at magnitudes greater than anticipated clinical exposure and in the presence of maximal reductions in maternal cholesterol and dose-dependent reductions in fetal cholesterol.


Asunto(s)
Anticuerpos Antiidiotipos/sangre , Anticuerpos Monoclonales Humanizados/administración & dosificación , Colesterol/sangre , Desarrollo Fetal/fisiología , Intercambio Materno-Fetal/fisiología , Serina Endopeptidasas/sangre , Animales , Anticuerpos Monoclonales Humanizados/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Desarrollo Fetal/efectos de los fármacos , Intercambio Materno-Fetal/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Proproteína Convertasa 9 , Ratas , Ratas Sprague-Dawley
3.
Bioorg Med Chem Lett ; 24(17): 4187-91, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25091930

RESUMEN

The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.


Asunto(s)
Bencimidazoles/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Fosfatos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Dominio Catalítico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil/metabolismo , Relación Estructura-Actividad
4.
PLoS One ; 19(2): e0298240, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38315680

RESUMEN

PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a repeat-dose PKPD (0.01-0.3 mg/kg/dose) and GLP toxicity study (0.1-3 mg/kg/dose). PF-07209960 showed dose dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. Release of cytokines IL-6, IFNγ, and IL-10 were detected, which peaked at 72 hours postdose. There was PF-07209960-related mortality at ≥1 mg/kg. At scheduled necropsy, microscopic findings were generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively.


Asunto(s)
Anticuerpos Monoclonales , Receptor de Muerte Celular Programada 1 , Animales , Macaca fascicularis , Interleucina-15 , Administración Intravenosa , Citocinas , Inhibidores de Puntos de Control Inmunológico
5.
Drug Metab Dispos ; 41(9): 1598-609, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23792813

RESUMEN

Drug-drug interactions (DDIs) between therapeutic proteins (TPs) and small-molecule drugs have recently drawn the attention of regulatory agencies, the pharmaceutical industry, and academia. TP-DDIs are mainly caused by proinflammatory cytokine or cytokine modulator-mediated effects on the expression of cytochrome P450 enzymes. To build consensus among industry and regulatory agencies on expectations and challenges in this area, a working group was initiated to review the preclinical state of the art. This white paper represents the observations and recommendations of the working group on the value of in vitro human hepatocyte studies for the prediction of clinical TP-DDI. The white paper was developed following a "Workshop on Recent Advances in the Investigation of Therapeutic Protein Drug-Drug Interactions: Preclinical and Clinical Approaches" held at the Food and Drug Administration White Oak Conference Center on June 4 and 5, 2012. Results of a workshop poll, cross-laboratory data comparisons, and the overall recommendations of the in vitro working group are presented herein. The working group observed that evaluation of TP-DDI for anticytokine monoclonal antibodies is currently best accomplished with a clinical study in patients with inflammatory disease. Treatment-induced changes in appropriate biomarkers in phase 2 and 3 studies may indicate the potential for a clinically measurable treatment effect on cytochrome P450 enzymes. Cytokine-mediated DDIs observed with anti-inflammatory TPs cannot currently be predicted using in vitro data. Future success in predicting clinical TP-DDIs will require an understanding of disease biology, physiologically relevant in vitro systems, and more examples of well conducted clinical TP-DDI trials.


Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Proteínas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Evaluación Preclínica de Medicamentos , Industria Farmacéutica , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Proteínas/farmacología , Estados Unidos , United States Food and Drug Administration
6.
Proc Natl Acad Sci U S A ; 107(20): 9446-51, 2010 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-20439741

RESUMEN

Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC(50) = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC(50) = 4.7 +/- 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC(50) value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Modelos Moleculares , Neoplasias/metabolismo , Pirazoles/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Quinasas p21 Activadas/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Pirazoles/química , Pirazoles/metabolismo , Pirroles/química , Pirroles/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho
7.
J Pharmacol Exp Ther ; 341(3): 702-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22414855

RESUMEN

In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (k(on) and k(off)), internalization of the drug-target complex (k(int)), target degradation rate (k(deg)), and target abundance (R(0)), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1- to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Simulación por Computador , Modelos Biológicos , Receptores de Activinas Tipo I/inmunología , Animales , Anticuerpos Monoclonales Humanizados , Ensayos Clínicos Fase I como Asunto , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Endotelio Vascular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Haplorrinos , Humanos , Inmunoglobulina G/inmunología , Ratones , Resonancia por Plasmón de Superficie , Venas Umbilicales
8.
Biomarkers ; 17(2): 125-33, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22188260

RESUMEN

The expression patterns and functional roles of three osteopontin splice variants (OPNa, b, and c) in cancer metastasis and progression are not well understood due to the lack of reliable assays to differentiate the isoforms. We have developed a mass spectrometric method to quantify OPN isoforms in human plasma. The method is based on the immunocapture of all OPN isoforms, followed by MRM-MS analysis of isoform-specific tryptic peptides. We were able to simultaneously identify and quantify all three isoforms in the plasma of 10 healthy individuals and 10 non-small cell lung cancer (NSCLC) patients. Our results show that none of the OPN splice variants is cancer specific. However, OPNa, the major isoform in healthy and NSCLC plasma, is substantially elevated in NSCLC patients, whereas OPNb and OPNc are at equivalent levels in two populations.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Osteopontina/sangre , ARN Neoplásico/genética , Empalme Alternativo/genética , Secuencia de Aminoácidos , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Exones , Humanos , Inmunoprecipitación , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Espectrometría de Masas , Datos de Secuencia Molecular , Osteopontina/genética , Fragmentos de Péptidos/análisis , Isoformas de Proteínas , Estructura Terciaria de Proteína , Estados Unidos
9.
Drug Metab Dispos ; 39(10): 1779-83, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21768274

RESUMEN

Increasing use of therapeutic proteins (TPs) in polypharmacy settings calls for more in-depth understanding of the biological interactions that can lead to increased toxicity or loss of pharmacological effect. Factors such as patient population, medications that are likely to be coadministered in that population, clearance mechanisms of a TP, and concomitant drugs have to be taken into account to determine the potential for drug-drug interactions (DDIs). The most well documented TP DDI mechanism involves cytokine-mediated changes in drug-metabolizing enzymes. Because of the limitations of the current preclinical models for addressing this type of DDI, clinical evaluation is currently the most reliable approach. Other DDI mechanisms need to be addressed on a case-by-case basis. These include altered clearance of TPs resulting from the changes in the target protein levels by the concomitant medication, displacement of TPs from binding proteins, modulation of Fcγ receptor expression, and others. The purpose of this review is to introduce the approach used by Pfizer scientists for evaluation of the DDI potential of novel TP products during drug discovery and development.


Asunto(s)
Productos Biológicos/farmacocinética , Productos Biológicos/uso terapéutico , Preparaciones Farmacéuticas/metabolismo , Proteínas/farmacocinética , Proteínas/uso terapéutico , Productos Biológicos/efectos adversos , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Humanos , Proteínas/efectos adversos
10.
Cancer Immunol Res ; 9(10): 1141-1157, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34376502

RESUMEN

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m, demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and single-cell RNA-sequencing analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from patients with cancer was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, our findings showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD1+ TILs.See related Spotlight by Felices and Miller, p. 1110.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias del Colon/terapia , Inmunoterapia , Interleucina-15/uso terapéutico , Melanoma Experimental/terapia , Animales , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Modelos Animales de Enfermedad , Humanos , Interleucina-15/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/inmunología , Ingeniería de Proteínas , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico
11.
Bioorg Med Chem Lett ; 20(7): 2210-4, 2010 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-20207139

RESUMEN

Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Isomerasa de Peptidilprolil/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Modelos Moleculares , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil/química , Unión Proteica , Relación Estructura-Actividad
12.
Mol Cancer Ther ; 19(10): 2105-2116, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32847983

RESUMEN

Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones
13.
Mol Cancer Ther ; 7(8): 2394-404, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18723486

RESUMEN

Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G(1) checkpoint. In these tumors, however, the S-G(2) checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a "synthetic lethal" response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K(i) of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents.


Asunto(s)
Benzodiazepinonas/farmacología , Daño del ADN , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/efectos de los fármacos , Pirazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cromatografía Liquida , Desoxicitidina/análogos & derivados , Desoxicitidina/antagonistas & inhibidores , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Histonas/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Fosforilación , Ratas , Ratas Sprague-Dawley , Fase S/efectos de los fármacos , Espectrometría de Masas en Tándem , Gemcitabina
14.
J Immunother Cancer ; 7(1): 105, 2019 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-30992085

RESUMEN

The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. antibodies targeting immune checkpoints, bispecific antibodies, and chimeric antigen receptor [CAR]-T cells), is raising questions on their potential immunogenicity and effects on treatment. In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related to their immunogenicity, and discuss the reported incidence of anti-drug antibodies (ADA) as well as their clinical relevance in patients with cancer. In addition, we discuss the impact of the administration route and potential strategies to reduce the incidence of ADA and manage treated patients. Analysis of published reports indicated that the risk of immunogenicity did not appear to correlate with the MOA of anti-programmed death 1 (PD-1)/PD-ligand 1 monoclonal antibodies nor to substantially affect treatment with most of these agents in the majority of patients evaluated to date. Treatment with B-cell depleting agents appears associated with a low risk of immunogenicity. No significant difference in ADA incidence was found between the intravenous and subcutaneous administration routes for a panel of non-oncology IMD antibodies. Additionally, while the data suggest a higher likelihood of immunogenicity for antibodies with T-cell or antigen-presenting cell (APC) targets versus B-cell targets, it is possible to have targets expressed on APCs or T cells and still have a low incidence of immunogenicity.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Enfermedades del Sistema Inmune/inmunología , Inmunoterapia Adoptiva/efectos adversos , Depleción Linfocítica/efectos adversos , Neoplasias/terapia , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Humanos , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades del Sistema Inmune/epidemiología , Enfermedades del Sistema Inmune/prevención & control , Inmunosupresores/uso terapéutico , Inmunoterapia Adoptiva/métodos , Incidencia , Depleción Linfocítica/métodos , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Quiméricos de Antígenos/inmunología , Resultado del Tratamiento
15.
Sci Rep ; 9(1): 8420, 2019 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-31182754

RESUMEN

Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC50 = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC50 = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.


Asunto(s)
Anticuerpos Biespecíficos/inmunología , Complejo CD3/inmunología , Claudinas/inmunología , Inmunoconjugados/uso terapéutico , Neoplasias Pancreáticas/terapia , Neoplasias Gástricas/terapia , Adenocarcinoma/terapia , Animales , Carcinoma Ductal Pancreático/terapia , Línea Celular Tumoral , Humanos , Inmunoconjugados/sangre , Ratones , Neoplasias Pancreáticas/sangre , Ratas , Neoplasias Gástricas/sangre
17.
J Med Chem ; 49(11): 3362-7, 2006 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-16722655

RESUMEN

Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).


Asunto(s)
Indenos/síntesis química , Morfolinas/síntesis química , Pirimidinas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Técnicas In Vitro , Indenos/química , Indenos/farmacología , Fosfatos de Inositol/biosíntesis , Masculino , Morfolinas/química , Morfolinas/farmacología , Orquiectomía , Hipófisis/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/antagonistas & inhibidores , Testosterona/metabolismo
18.
Cytometry B Clin Cytom ; 90(2): 191-8, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25914284

RESUMEN

BACKGROUND: Interleukin-7 receptor α (IL-7Rα) is associated with autoimmune disease. Blocking its activation by interleukin-7 (IL-7) with a therapeutic monoclonal antibody may reduce pathogenic T cells and effectively control the autoimmune response in these disorders. METHODS: Two flow cytometry-based assays were developed and implemented to evaluate the interaction between cell surface IL-7Rα and an anti-IL-7Rα monoclonal antibody (Ab1). The receptor occupancy assay utilized competing and noncompeting commercial detection antibodies for "free" and "total" IL-7Rα, respectively. STAT5 phosphorylation (pSTAT5) was measured as a proximal biomarker of IL-7Rα inhibition by Ab1. RESULTS: Monkeys administered Ab1 had no free IL-7Rα detectable on the CD3+ T cell surface at 0.25 hours postdose through day 4, in all treatment groups. Ab1 treatment resulted in a significant reduction in total IL-7Rα, dropping to 53%, 44%, and 55% on day 4 at 0.3, 3, and 30 mg/kg, respectively, compared to predose levels. There were treatment-related decreases in the ability of IL-7 to induce STAT5 phosphorylation in both CD4+ and CD8+ T cells in monkey blood samples from all treated animals from 0.25 hours through Day 4 postdose. CONCLUSIONS: The nonclinical receptor occupancy assay was developed and applied to detect free and total IL-7Rα on the surface of CD3+ T cells in cynomolgus monkeys treated with Ab1. The results showed good correlation with the phosphorylation of STAT5 and serum concentration of Ab1. The approach for IL-7Rα occupancy and pSTAT5 measurements established in monkeys can be utilized in clinical trials for pharmacokinetic/pharmacodynamic evaluation of Ab1 effect in humans.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Citometría de Flujo , Receptores de Interleucina-7/inmunología , Factor de Transcripción STAT5/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Enfermedades Autoinmunes/terapia , Humanos , Interleucina-7/inmunología , Macaca fascicularis/inmunología , Fosforilación , Receptores de Interleucina-7/antagonistas & inhibidores , Factor de Transcripción STAT5/antagonistas & inhibidores
19.
Mol Cancer Ther ; 15(11): 2698-2708, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27582525

RESUMEN

Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. ©2016 AACR.


Asunto(s)
Antineoplásicos/farmacología , Moléculas de Adhesión Celular/antagonistas & inhibidores , Inmunoconjugados/farmacología , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Femenino , Expresión Génica , Humanos , Inmunoconjugados/química , Lisosomas , Ratones , Mitosis/efectos de los fármacos , Mitosis/genética , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Ensayos Antitumor por Modelo de Xenoinjerto
20.
AAPS J ; 15(4): 1141-54, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23990500

RESUMEN

A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA-drug complex. The model also provides a mean to estimate putative concentration-time profiles for ADA, ADA-drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose-response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/fisiología , Modelos Teóricos , Animales , Anticuerpos Monoclonales/inmunología , Relación Dosis-Respuesta Inmunológica , Macaca fascicularis , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología
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