RESUMO
Polatuzumab vedotin is a CD79b-directed antibody-drug conjugate that targets B cells and delivers the cytotoxic payload monomethyl auristatin E (MMAE). The phase III POLARIX study (NCT03274492) evaluated polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) as first-line treatment of diffuse large B-cell lymphoma (DLBCL). To examine dosing decisions for this regimen, population pharmacokinetic (popPK) analysis, using a previously developed popPK model, and exposure-response (ER) analysis, were performed. The popPK analysis showed no clinically meaningful relationship between cycle 6 (C6) antibody-conjugated (acMMAE)/unconjugated MMAE area under the concentration-time curve (AUC) or maximum concentration, and weight, sex, ethnicity, region, mild or moderate renal impairment, mild hepatic impairment, or other patient and disease characteristics. In the ER analysis, C6 acMMAE AUC was significantly associated with longer progression-free and event-free survival (both p = 0.01). An increase of <50% in acMMAE/unconjugated MMAE exposure did not lead to a clinically meaningful increase in adverse events of special interest. ER data and the benefit-risk profile support the use of polatuzumab vedotin 1.8 mg/kg once every 3 weeks with R-CHP for six cycles in patients with previously untreated DLBCL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Doxorrubicina/farmacocinética , Doxorrubicina/análogos & derivados , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Ciclofosfamida/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/administração & dosagem , Prednisona/farmacocinética , Prednisona/uso terapêutico , Rituximab/farmacocinética , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Adulto , Área Sob a Curva , Modelos Biológicos , Imunoconjugados/farmacocinética , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Relação Dose-Resposta a Droga , Intervalo Livre de ProgressãoRESUMO
Background: Measuring pharmacodynamic biomarkers near the therapeutic site of action presents considerable challenges for sites with limited matrix volume or difficult access. Bioanalytical method qualification requires the use of numerous matrix samples, which is problematic for rare matrices. The aim of this study was to design and implement a streamlined, fit-for-purpose strategy for qualification of biomarker assays in rare matrices. Materials & methods: A multiplexed biomarker immunoassay was developed in human aqueous humor. Results: Our strategy was successfully implemented, providing characterization of assay performance while reducing number of samples in assay qualification. Our assay was used in clinical trial support for an ophthalmic drug candidate. Conclusion: Our results indicate this approach can be applied to other early stage drug development programs facing similar challenges.
Bioanalytical assay development and qualification requires the use of numerous matrix samples, which is problematic for rare matrices. We designed and successfully implemented a streamlined strategy for qualification of biomarker assays in rare matrices.
Assuntos
Humor Aquoso , Biomarcadores , Humor Aquoso/química , Humor Aquoso/metabolismo , Humanos , Biomarcadores/análise , Biomarcadores/metabolismo , Imunoensaio/métodosRESUMO
The favorable benefit-risk profile of polatuzumab vedotin, as demonstrated in a pivotal Phase Ib/II randomized study (GO29365; NCT02257567), coupled with the need for effective therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), prompted the need to accelerate polatuzumab vedotin development. An integrated, fit-for-purpose clinical pharmacology package was designed to support regulatory approval. To address key clinical pharmacology questions without dedicated clinical pharmacology studies, we leveraged non-clinical and clinical data for polatuzumab vedotin, published clinical data for brentuximab vedotin, a similar antibody-drug conjugate, and physiologically based pharmacokinetic and population pharmacokinetic modeling approaches. We review strategies and model-informed outcomes that contributed to regulatory approval of polatuzumab vedotin plus bendamustine and rituximab in R/R DLBCL. These strategies made polatuzumab vedotin available to patients earlier than previously possible; depending on the strength of available data and the regulatory/competitive environment, they may also prove useful in accelerating the development of other agents.
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Farmacologia Clínica , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológicoRESUMO
This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non-Asian patients with previously untreated diffuse large B-cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non-Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody-conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non-Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%-7.0% and 17.3%-19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non-Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Humanos , Anticorpos Monoclonais/farmacocinética , Ásia , Imunoconjugados/farmacocinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Ensaios Clínicos Fase III como AssuntoRESUMO
Polatuzumab vedotin, marketed under the trade name POLIVY®, is a CD79b-targeted antibody-drug conjugate that preferentially delivers a potent anti-mitotic agent (monomethyl auristatin E) to B cells, resulting in anti-cancer activity against B-cell malignancies. In 2019, polatuzumab vedotin in combination with rituximab and bendamustine was approved by the United States Food and Drug Administration for the treatment of adult patients with diffuse large B-cell lymphoma who have received at least two prior therapies. Recent Health Authority guidance recommendations for submitting an Integrated Summary of Immunogenicity were followed including a comprehensive immunogenicity risk assessment, bioanalytical strategy, and immunogenicity data to support the registration of polatuzumab vedotin. Key components of the polatuzumab vedotin Integrated Summary of Immunogenicity and data are presented. Validated semi-homogeneous bridging enzyme-linked immunosorbent assays were used to detect anti-drug antibodies (ADA) to polatuzumab vedotin and characterize the immune response in patients with non-Hodgkin's lymphoma. The overall incidence of ADA observed for polatuzumab vedotin was low across seven clinical trials. The low incidence of ADA is likely due to the mechanism of action of polatuzumab vedotin that involves targeting and killing of B cells, thereby limiting the development to plasma cells and ADA secretion. Furthermore, patients are co-medicated with rituximab, which also targets B cells and results in B-cell depletion. Therefore, the immunogenicity risk is considered low and not expected to impact the polatuzumab vedotin benefit/risk profile.
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Estados Unidos , Adulto , Humanos , Rituximab/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoconjugados/efeitos adversos , Linfoma não Hodgkin/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológicoAssuntos
Anticorpos/uso terapêutico , Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Imunoconjugados/uso terapêutico , Lectinas Tipo C/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Receptores Mitogênicos/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos/administração & dosagem , Anticorpos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Lectinas Tipo C/imunologia , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Receptores Mitogênicos/imunologia , Adulto JovemRESUMO
PURPOSE: The established two-analyte integrated population pharmacokinetic model was applied to assess the impact of intrinsic/extrinsic factors on the pharmacokinetics (PK) of polatuzumab vedotin (pola) in patients with non-Hodgkin lymphoma (NHL) following bodyweight-based dosing. METHODS: Model simulations based on individual empirical Bayes estimates were used to evaluate the impact of intrinsic/extrinsic factors as patient subgroups on Cycle 6 exposures. Intrinsic factors included bodyweight, age, sex, hepatic and renal functions. Extrinsic factors included rituximab/obinutuzumab or bendamustine combination with pola and manufacturing process. The predicted impact on exposures along with the established exposure-response relationships were used to assess clinical relevance. RESULTS: No clinically meaningful differences in Cycle 6 pola exposures were found for the following subgroups: bodyweight 100-146 kg versus 38-<100 kg, age ≥ 65 years versus <65 years, female versus male, mild hepatic impairment versus normal, mild-to-moderate renal impairment versus normal. Co-administration of rituximab/obinutuzumab or bendamustine, and change in the pola manufacturing process, also had no meaningful impact on PK. CONCLUSIONS: In patients with NHL, bodyweight-based dosing is adequate, and no further dose adjustment is recommended for the heavier subgroup (100-146 kg). In addition, no dose adjustments are recommended for other subgroups based on intrinsic/extrinsic factors evaluated.
Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Imunoconjugados/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Modelos Biológicos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Peso Corporal , Ensaios Clínicos como Assunto , Simulação por Computador , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Imunoconjugados/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
PURPOSE: The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. METHODS: Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. RESULTS: Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola. CONCLUSIONS: Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais , Imunoconjugados , Linfoma de Células B , Rituximab , Administração Intravenosa , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/farmacocinéticaRESUMO
PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Distribuição Tecidual , Resultado do TratamentoRESUMO
A two-analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non-Hodgkin lymphoma. A two-compartment model with a nonspecific, time-dependent linear clearance, a linear time-dependent exponentially declining clearance, and a Michaelis-Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two-compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.
Assuntos
Anticorpos Monoclonais/farmacocinética , Imunoconjugados/farmacocinética , Linfoma não Hodgkin/tratamento farmacológico , Modelos Biológicos , Anticorpos Monoclonais/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/administração & dosagem , Modelos Lineares , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Polatuzumab vedotin is an antibody-drug conjugate (ADC) being developed for non-Hodgkin's lymphoma. It contains a humanized anti-CD79b IgG1 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti-mitotic agent. Polatuzumab vedotin binds to human CD79b only. Therefore, a surrogate ADC that binds to cynomolgus monkey CD79b was used to determine CD79b-mediated pharmacological effects in the monkey and to enable first-in-human clinical trials. EXPERIMENTAL APPROACH: Polatuzumab vedotin, the surrogate ADC, and the corresponding antibodies were evaluated in different assays in vitro and in animals. In vitro assessments included binding to peripheral blood mononuclear cells from different species, binding to a human and monkey CD79b-expressing cell line, binding to human Fcγ receptors, and stability in plasma across species. In vivo, ADCs were assessed for anti-tumour activity in mice, pharmacokinetics/pharmacodynamics in monkeys, and toxicity in rats and monkeys. KEY RESULTS: Polatuzumab vedotin and surrogate ADC bind with similar affinity to human and cynomolgus monkey B cells, respectively. Comparable in vitro plasma stability, in vivo anti-tumour activity, and mouse pharmacokinetics were also observed between the surrogate ADC and polatuzumab vedotin. In monkeys, only the surrogate ADC showed B-cell depletion and B-cell-mediated drug disposition, but both ADCs showed similar MMAE-driven myelotoxicity, as expected. CONCLUSIONS AND IMPLICATIONS: The suitability of the surrogate ADC for evaluation of CD79b-dependent pharmacology was demonstrated, and anti-tumour activity, pharmacokinetics/pharmacodynamics, and toxicity data with both ADCs supported the entry of polatuzumab vedotin into clinical trials.
Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Antígenos CD79/antagonistas & inibidores , Imunoconjugados/farmacologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/química , Antineoplásicos/imunologia , Sítios de Ligação/efeitos dos fármacos , Linfoma de Burkitt/patologia , Antígenos CD79/imunologia , Linhagem Celular , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Macaca fascicularis , Masculino , Camundongos , Camundongos SCID , Conformação Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Ratos , Ratos Sprague-Dawley , Receptores de IgG , Relação Estrutura-AtividadeRESUMO
Aim: To evaluate the clinical immunogenicity of eight antibody-drug conjugates (ADCs), multi-domain biotherapeutics that could theoretically pose a greater immunogenicity risk than monoclonal antibodies (mAbs) because they contain non-natural structural motifs. Methodology & results: Immunogenicity strategies and assays for these ADCs included those commonly used for conventional biotherapeutics with additional characterization. A tiered approach was adopted for testing Phase I and II clinical study samples with screening, confirmatory assays and additional domain characterization. Antidrug antibody incidences with these ADCs were within those reported for mAb biotherapeutics with no apparent impact on clinical outcomes. Conclusion: These data suggest that the ADC hapten-like structure across these eight ADCs does not appear to increase patient immune responses beyond those generally observed for mAb biotherapeutics.
Assuntos
Ensaios Clínicos como Assunto , Imunoconjugados/imunologia , Técnicas Imunológicas , HumanosRESUMO
Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.
Assuntos
Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Doença Aguda , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Área Sob a Curva , Benzodiazepinas/imunologia , Benzodiazepinas/uso terapêutico , Humanos , Imunoconjugados/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Lectinas Tipo C/imunologia , Leucemia Mieloide/sangue , Macaca fascicularis , Taxa de Depuração Metabólica , Camundongos , Pirróis/imunologia , Pirróis/uso terapêutico , Ratos , Receptores Mitogênicos/imunologia , Especificidade da EspécieRESUMO
Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Imunoconjugados/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminobenzoatos/administração & dosagem , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Rituximab/efeitos adversos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologiaRESUMO
BACKGROUND AND PURPOSE: CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys. EXPERIMENTAL APPROACH: Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro. KEY RESULTS: Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity. CONCLUSIONS AND IMPLICATIONS: The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics.
Assuntos
Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Antígenos CD79/imunologia , Oligopeptídeos/farmacologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Reações Antígeno-Anticorpo , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Masculino , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3â+â3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD79/imunologia , Imunoconjugados/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Antígenos CD79/biossíntese , Esquema de Medicação , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RituximabRESUMO
PURPOSE: A semi-mechanistic multiple-analyte population pharmacokinetics (PK) model was developed to describe the complex relationship between the different analytes of monomethyl auristatin E (MMAE) containing antibody-drug conjugates (ADCs) and to provide insight regarding the major pathways of conjugate elimination and unconjugated MMAE release in vivo. METHODS: For an anti-CD79b-MMAE ADC the PK of total antibody (Tab), conjugate (evaluated as antibody conjugated MMAE or acMMAE), and unconjugated MMAE were quantified in cynomolgus monkeys for single (0.3, 1, or 3 mg/kg), and multiple doses (3 or 5 mg/kg, every-three-weeks for 4 doses). The PK data of MMAE in cynomolgus monkeys, after intravenous administration of MMAE at single doses (0.03 or 0.063 mg/kg), was included in the analysis. A semi-mechanistic model was developed and parameter estimates were obtained by simultaneously fitting the model to all PK data using a hybrid ITS-MCPEM method. RESULTS: The final model well described the observed Tab, acMMAE and unconjugated MMAE concentration-time profiles. Analysis suggested that conjugate is lost via both proteolytic degradation and deconjugation, while unconjugated MMAE in systemic circulation appears to be mainly released via proteolytic degradation of the conjugate. CONCLUSIONS: Our model improves the understanding of ADC catabolism, which may provide useful insights when designing future ADCs.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Modelos Biológicos , Oligopeptídeos/farmacocinética , Administração Intravenosa , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Biotransformação , Macaca fascicularis , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , ProteóliseRESUMO
BACKGROUND: Antibody-drug conjugates (ADCs) such as Kadcyla™ (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components. RESULTS: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation. CONCLUSION: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais/imunologia , Fenômenos Imunogenéticos , Maitansina/análogos & derivados , Ado-Trastuzumab Emtansina , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Macaca fascicularis , Maitansina/administração & dosagem , Maitansina/imunologia , Maitansina/uso terapêutico , TrastuzumabRESUMO
BACKGROUND: Antibody-drug conjugates (ADCs) combine the characteristics of large-molecule biologics and small-molecule drugs and are heterogeneous mixtures that can biotransform in vivo, resulting in additional complexity. ADC bioanalytical strategies require novel analytical methods, as well as existing large- and small-molecule methods. Because ADCs in late-stage clinical development are relatively new, regulatory guidelines and standard industry best practices for developing strategies for bioanalytical PK assays are still being established. RESULTS: A PK assay strategy was developed that included comprehensive novel reagent and assay characterization approaches for the ADC ado-trastuzumab emtansine (T-DM1). CONCLUSION: The bioanalytical strategy was successfully applied to the drug development of T-DM1 and ensured that key analytes were accurately measured in support of nonclinical and clinical development.
Assuntos
Anticorpos Monoclonais Humanizados/análise , Anticorpos Monoclonais/análise , Ensaio de Imunoadsorção Enzimática , Imunoconjugados/análise , Maitansina/análogos & derivados , Ado-Trastuzumab Emtansina , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados/metabolismo , Anticorpos Monoclonais Humanizados/farmacocinética , Cromatografia Líquida , Desenho de Fármacos , Imunoconjugados/farmacocinética , Espectrometria de Massas , Maitansina/análise , Maitansina/metabolismo , Maitansina/farmacocinética , TrastuzumabRESUMO
BACKGROUND: Antibody-drug conjugates (ADCs) are a new class of cancer therapeutics that deliver potent cytotoxins specifically to tumors to minimize systemic toxicity. However, undesirable release of covalently linked drugs in circulation can affect safety and efficacy. The objective of this manuscript was to propose and assess the assays that allow for the characterization of the drug deconjugation in plasma/serum. RESULTS: ADCs of three main drug conjugation platforms, linked via lysine, site-specific engineered cysteine or reduced interchain disulfide cysteine residues, were analyzed using affinity capture for sample enrichment coupled with LC-MS or hydrophobic interaction chromatography-UV for detection. These novel approaches enabled measurement of the relative abundance of individual ADC species with different drug-to-antibody ratios, while maintaining their structural integrity. CONCLUSION: The characterization data generated by affinity capture LC-MS or hydrophobic interaction chromatography-UV provided critical mechanistic insights into understanding the stability and bioactivity of ADCs in vivo, and also helped the development of appropriate quantitative ELISAs.