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1.
Pharmacol Res Perspect ; 8(2): e00573, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32125783

RESUMO

A phage-derived human monoclonal antibody against VEGF-C was developed as a potential anti-tumor therapeutic and exhibited fast clearance in preclinical species, with notably faster clearance in serum than in plasma. The purpose of this work was to understand the factors contributing to its fast clearance. In vitro incubations in animal and human blood, plasma, and serum were conducted with radiolabeled anti-VEGF-C to determine potential protein and cell-based interactions with the antibody as well as any matrix-dependent recovery dependent upon the matrix. A tissue distribution study was conducted in mice with and without heparin infusion in order to identify a tissue sink and determine whether heparin could affect antibody recovery from serum and/or plasma. Incubation of radiolabeled anti-VEGF-C in human and animal blood, plasma, or serum revealed that the antibody formed a complex with an endogenous protein, likely VEGF-C. This complex was trapped within the blood clot during serum preparation from blood, but not within the blood cell pellet during plasma preparation. Low level heparin infusion in mice slowed down clot formation during serum preparation and allowed for better recovery of the radiolabeled antibody in serum. No tissue sink was found in mice. Thus, during this characterization, we determined that the blood sampling matrix greatly impacted the amount of antibody recovered in the samples, therefore, altering its derived pharmacokinetic parameters. Target biology should be considered when selecting appropriate sampling matrices for PK analysis.

2.
Bioorg Med Chem Lett ; 30(4): 126907, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31902710

RESUMO

Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.

3.
ChemMedChem ; 15(1): 17-25, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31674143

RESUMO

The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

4.
Transl Vis Sci Technol ; 8(6): 1, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31695962

RESUMO

Purpose: Development of therapeutics for retinal disease with improved durability is hampered by inadequate understanding of pharmacokinetic (PK) drivers following intravitreal injection. Previous work shows that hydrodynamic radius is correlated with vitreal half-life over the range of 3 to 7 nm, and that charge and hydrophobicity influence systemic clearance. Better understanding the molecular attributes affecting vitreal elimination half-life enables improved design of therapeutics and enhances clinical translatability. Methods: Impacts of charge and hydrophobicity on vitreal PK in the rabbit were systematically assessed using antibody and antibody fragment (Fab) variant series, including ranibizumab, altered through amino acid changes in hypervariable regions of the light chain. The impact of molecule size on vitreal PK was assessed in the rabbit, nonhuman primate, and human for a range of molecules (1-45 nm, net charge -1324 to +22.9 in rabbit), including published and internal data. Results: No correlation was observed between vitreal PK and charge or hydrophobicity. Equivalent rabbit vitreal PK was observed for ranibizumab and its variants with isoelectric points (pI) in the range of 6.8 to 10.2, and hydrophobicities of the variable domain unit (FvHI) between 1009 and 1296; additional variant series had vitreal PK similarly unaffected by pI (5.4-10.2) and FvHI (1004-1358). Strong correlations were observed between vitreal half-life and hydrodynamic radius for preclinical species (R 2 = 0.8794-0.9366). Conclusions: Diffusive properties of soluble large molecules, as quantified by hydrodynamic radius, make a key contribution to vitreal elimination, whereas differences in charge or hydrophobicity make minor or negligible contributions. Translational Relevance: These results support estimation of vitreal elimination rates based on molecular size in relevant preclinical species and humans.

5.
PLoS One ; 14(10): e0224096, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661493

RESUMO

Staphylococcus aureus (S. aureus) infections are a leading cause of death by an infectious agent. Survival within host phagocytic cells is one mechanism by which S. aureus evades antibiotic treatment. A novel THIOMAB™ antibody-antibiotic conjugate (TAC) strategy was developed to kill S. aureus intracellularly and mitigate the spread of infection. In this report, we used a longitudinal whole-body bioluminescence imaging method to study the antibacterial dynamics of TAC alone or in combination with vancomycin in a mouse infection model. Injections of stably luminescent S. aureus bacteria into mice resulted in exponential increases in whole body bioluminescence with a reduction in body weight and survival rate. Vancomycin, a standard-of-care antibiotic, suppressed bacterial growth in mice. However, bacterial growth rebounded in these animals once treatment was discontinued. In contrast, single dose of TAC showed rapid reduction of bioluminescence intensity, which persisted for up to 19 days. The combination of TAC and vancomycin achieved a more sustained and significantly greater reduction of bioluminescence compared with vancomycin alone. In summary, the present study showed an imaging method to longitudinally assess antibacterial drug dynamics in mice and demonstrated that TAC monotherapy or in combination with vancomycin had superior and sustained activity compared to vancomycin alone.

6.
MAbs ; 11(6): 1162-1174, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31219754

RESUMO

DSTA4637S, a novel THIOMAB™ antibody-antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy for complicated S. aureus bloodstream infections. DSTA4637S is composed of a monoclonal THIOMABTM IgG1 recognizing S. aureus linked to a rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. The pharmacokinetics (PK) of DSTA4637A (a liquid formulation of DSTA4637S) and its unconjugated antibody MSTA3852A were characterized in rats and monkeys. Systemic concentrations of three analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured to describe complex TAC PK in nonclinical studies. In rats and monkeys, following intravenous administration of a single dose of DSTA4637A, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential, characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested, and ac-dmDNA31 cleared 2-3 times faster than TAb. Unconjugated dmDNA31 plasma concentrations were low (<4 ng/mL) in every study regardless of dose. In this report, an integrated semi-mechanistic PK model for two analytes (TAb and ac-dmDNA31) was successfully developed and was able to well describe the complicated DSTA4637A PK in mice, rats and monkeys. DSTA4637S human PK was predicted reasonably well using this model with allometric scaling of PK parameters from monkey data. This work provides insights into PK behaviors of DSTA4637A in preclinical species and informs clinical translatability of these observed results and further clinical development. Abbreviations: ADC: Antibody-drug conjugate; AUCinf: time curve extrapolated to infinity; ac-dmDNA31: antibody-conjugated dmDNA31; Cmax: maximum concentration observed; DAR: drug-to-antibody ratio; CL: clearance; CLD: distribution clearance; CL1: systemic clearance of all DAR species; kDC: deconjugation rate constant; PK: Pharmacokinetics; IV: Intravenous; IgG: Immunoglobulin G; mAb: monoclonal antibody; S. aureus: Staphylococcus aureus; TAC: THIOMABTM antibody-antibiotic conjugate; TDC: THIOMABTM antibody-drug conjugate; TAb: total antibody; t1/2, λz: terminal half-life; vc linker: valine-citrulline linker; Vss: volume of distribution at steady state; Vc: volume of distribution for the central compartment; Vp: the volume of distribution for the peripheral compartment.


Assuntos
Anticorpos Antibacterianos , Anticorpos Monoclonais , Imunoconjugados , Imunoglobulina G , Rifamicinas , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/farmacologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Macaca fascicularis , Masculino , Ratos , Ratos Sprague-Dawley , Rifamicinas/imunologia , Rifamicinas/farmacocinética , Rifamicinas/farmacologia
7.
Clin Transl Sci ; 12(5): 534-544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115997

RESUMO

Prediction of human pharmacokinetics (PK) based on preclinical information for antibody-drug conjugates (ADCs) provide important insight into first-in-human (FIH) study design. This retrospective analysis was conducted to identify an appropriate scaling method to predict human PK for ADCs from animal PK data in the linear range. Different methods for projecting human clearance (CL) from animal PK data for 11 ADCs exhibiting linear PK over the tested dose ranges were examined: multiple species allometric scaling (CL vs. body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent, and scaling from only cynomolgus monkey PK data. Two analytes of interest for ADCs, namely total antibody and conjugate (measured as conjugated drug or conjugated antibody), were assessed. Percentage prediction errors (PEs) and residual sum of squares (RSS) were compared across methods. Human CL was best estimated using cynomolgus monkey PK data alone and an allometric scaling exponent of 1.0 for CL. This was consistently observed for both conjugate and total antibody analytes. Other scaling methods either underestimated or overestimated human CL, or produced larger average absolute PEs and RSS. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 1.0 for CL and 1.0 for volume of distribution. In conclusion, results from this retrospective analysis of 11 ADCs indicate that allometric scaling of CL with an exponent of 1.0 using cynomolgus monkey PK data alone can successfully project human PK profiles of an ADC within linear range.

8.
Bioconjug Chem ; 30(5): 1356-1370, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30966735

RESUMO

This work discloses the first examples of antibody-drug conjugates (ADCs) that are constructed from linker-drugs bearing dimeric seco-CBI payloads (duocarmycin analogs). Several homogeneous, CD22-targeting THIOMAB antibody-drug conjugates (TDCs) containing the dimeric seco-CBI entities are shown to be highly efficacious in the WSU-DLCL2 and BJAB mouse xenograft models. Surprisingly, the seco-CBI-containing conjugates are also observed to undergo significant biotransformation in vivo in mice, rats, and monkeys and thereby form 1:1 adducts with the Alpha-1-Microglobulin (A1M) plasma protein from these species. Variation of both the payload mAb attachment site and length of the linker-drug is shown to alter the rates of adduct formation. Subsequent experiments demonstrated that adduct formation attenuates the in vitro antiproliferation activity of the affected seco-CBI-dimer TDCs, but does not significantly impact the in vivo efficacy of the conjugates. In vitro assays employing phosphatase-treated whole blood suggest that A1M adduct formation is likely to occur if the seco-CBI-dimer TDCs are administered to humans. Importantly, protein adduct formation leads to the underestimation of total antibody (Tab) concentrations using an ELISA assay but does not affect Tab values determined via an orthogonal LC-MS/MS method. Several recommendations regarding bioanalysis of future in vivo studies involving related seco-CBI-containing ADCs are provided based on these collective findings.


Assuntos
alfa-Globulinas/química , Antineoplásicos/farmacologia , Imunoconjugados/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Haplorrinos , Humanos , Imunoconjugados/química , Camundongos , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Artigo em Inglês | MEDLINE | ID: mdl-30910894

RESUMO

Staphylococcus aureus causes serious bacterial infections with high morbidity and mortality, necessitating the discovery of new antibiotics. DSTA4637S is a novel antibody-antibiotic conjugate designed to target intracellular S. aureus that is not adequately eliminated by current standard-of-care antibiotics. DSTA4637S is composed of an anti-S. aureus Thiomab human immunoglobulin G1 (IgG1) monoclonal antibody linked to a novel rifamycin-class antibiotic (4-dimethylaminopiperidino-hydroxybenzoxazino rifamycin [dmDNA31]) via a protease-cleavable linker. Phagocytic cells ingest DSTA4637S-bound S. aureus, and intracellular cathepsins cleave the linker, releasing dmDNA31and killing intracellular S. aureus This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 trial analyzed the safety, pharmacokinetics, and immunogenicity of DSTA4637S in healthy volunteers. Thirty healthy male and female volunteers, 18-65 years old, were randomized into five cohorts receiving single intravenous (i.v.) doses of 5, 15, 50, 100, and 150 mg/kg of DSTA4637S or placebo (4 active:2 placebo). Subjects were followed for 85 days after dosing. No subject withdrew from the study, and no serious or severe adverse events occurred. One moderate infusion-related reaction (150 mg/kg DSTA4637S) occurred. No clinically meaningful or dose-related changes in laboratory parameters or vital signs occurred. Pharmacokinetics of plasma DSTA4637S conjugate and serum DSTA4637S total antibody were dose proportional. Systemic exposure of unconjugated dmDNA31 was low. No DSTA4637S-induced anti-drug antibody responses were observed. DSTA4637S was generally safe and well tolerated as a single i.v. dose in healthy volunteers. DSTA4637S has a favorable safety and pharmacokinetic profile that supports future development as a novel therapeutic for S. aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02596399.).

10.
MAbs ; 11(2): 422-433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30550367

RESUMO

Bispecific antibody production using single host cells has been a new advancement in the antibody engineering field. We previously showed comparable in vitro biological activity and in vivo mouse pharmacokinetics (PK) for two novel single cell variants (v10 and v11) and one traditional dual cell in vitro-assembled anti-human epidermal growth factor receptor 2/CD3 T-cell dependent bispecific (TDB) antibodies. Here, we extended our previous work to assess single cell-produced bispecific variants of a novel TDB against FcRH5, a B-cell lineage marker expressed on multiple myeloma (MM) tumor cells. An in vitro-assembled anti- FcRH5/CD3 TDB antibody was previously developed as a potential treatment option for MM. Two bispecific antibody variants (designs v10 and v11) for manufacturing anti-FcRH5/CD3 TDB in single cells were compared to in vitro-assembled TDB in a dual-cell process to understand whether differences in antibody design and production led to any major differences in their in vitro biological activity, in vivo mouse PK, and PK/pharmacodynamics (PD) or immunogenicity in cynomolgus monkeys (cynos). The binding, in vitro potencies, in vitro pharmacological activities and in vivo PK in mice and cynos of these single cell TDBs were comparable to those of the in vitro-assembled TDB. In addition, the single cell and in vitro-assembled TDBs exhibited robust PD activity and comparable immunogenicity in cynos. Overall, these studies demonstrate that single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties, and support further development of single-cell production method for anti-FcRH5/CD3 TDBs and other single-cell bispecifics.


Assuntos
Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacocinética , Receptores Fc/química , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Complexo CD3/imunologia , Desenho de Fármacos , Humanos , Técnicas In Vitro , Macaca fascicularis , Camundongos , Mieloma Múltiplo , Linfócitos T/imunologia
11.
MAbs ; 10(8): 1312-1321, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183491

RESUMO

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 Espécie
12.
MAbs ; 10(7): 1131-1143, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30081725

RESUMO

DSTA4637A, a THIOMAB™ antibody-antibiotic conjugate targeting Staphylococcus aureus, has shown promising bactericidal activity in a mouse model. DSTA4637A consists of a monoclonal anti-S. aureus antibody with an average of two rifalogue antibiotic molecules, dmDNA31, linked to its light chains. The goal of this study was to develop a minimal physiologically-based pharmacokinetic (mPBPK) model to characterize the pharmacokinetic (PK) properties of three analytes of DSTA4637A (i.e., total antibody, antibody-conjugated dmDNA31, and unconjugated dmDNA31) in mice, and to predict pharmacokinetics of DSTA4637A analytes in humans, as well as to provide an initial assessment for potential PK drug-drug interactions (DDI) in clinical trials via cross-species scaling of the mPBPK model. In the proposed model, selected organs, including heart, liver, and kidney, were connected anatomically with plasma and lymph flows. Mouse plasma and tissue concentrations of the three analytes of DSTA4637A were fitted simultaneously to estimate the PK parameters. Cross-species scaling of the model was performed by integrating allometric scaling and human physiological parameters. The final mPBPK model was able to successfully capture PK profiles of three DSTA4637A analytes in mouse plasma and in investigated organs. The model predicted a steady-state peak unbound dmDNA31 concentration lower than 5% of the IC50 of dmDNA31 towards cytochrome P450 following 100 mg/kg weekly intravenous dose, which suggests a low risk of PK DDI in humans for DSTA4637A with co-administered cytochrome P450 substrates. The proposed mPBPK modeling and cross-species scaling approaches provide valuable tools that facilitate the understanding and translation of DSTA4637A disposition from preclinical species to humans.


Assuntos
Antibacterianos/farmacocinética , Anticorpos Monoclonais/farmacocinética , Imunoconjugados/farmacocinética , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/fisiologia , Animais , Antibacterianos/química , Anticorpos Antibacterianos/química , Anticorpos Monoclonais/química , Interações Medicamentosas , Feminino , Humanos , Imunoconjugados/química , Camundongos , Camundongos SCID , Modelos Animais , Modelos Biológicos
13.
MAbs ; 10(5): 738-750, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29757698

RESUMO

For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.


Assuntos
Algoritmos , Anticorpos Monoclonais/farmacocinética , Imunoconjugados/farmacocinética , Modelos Biológicos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Imunoconjugados/imunologia , Macaca fascicularis , Estudos Prospectivos , Especificidade da Espécie
14.
Mol Cancer Ther ; 16(5): 871-878, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28223423

RESUMO

A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871-8. ©2017 AACR.


Assuntos
Anticorpos/administração & dosagem , Benzodiazepinas/administração & dosagem , Imunoconjugados/administração & dosagem , Neoplasias/tratamento farmacológico , Pirróis/administração & dosagem , Animais , Anticorpos/química , Anticorpos/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/imunologia , Benzodiazepinas/química , Benzodiazepinas/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Dissulfetos/imunologia , Humanos , Imunoconjugados/química , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Pirróis/química , Pirróis/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Drug Discov Today Technol ; 21-22: 75-83, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27978991

RESUMO

Monoclonal antibodies (mAbs) are an important therapeutic class with complex pharmacology and interdependent pharmacokinetic (PK) and pharmacodynamics (PD) properties. Understanding the PK and PD of mAbs and their biological and mechanistic underpinnings are crucial in enabling their design and selection, designing appropriate efficacy and toxicity studies, translating PK/PD parameters to humans, and optimizing dose and regimen to maximize success in the clinic. Significant progress has been made in this field however many critical questions still remain. This article gives a brief overview of the PK and PD of mAbs, factors that influence them, and areas of ongoing inquiry. Current tools and translational approaches to predict the PK/PD of mAbs in humans are also discussed.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Modelos Biológicos , Animais , Humanos , Pesquisa Médica Translacional
16.
Regul Toxicol Pharmacol ; 82: 1-13, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27773754

RESUMO

Antibody drug conjugates (ADC) consist of potent cytotoxic drugs conjugated to antibodies via chemical linkers, which enables specific targeting of tumor cells while reducing systemic exposure to the cytotoxic drug and improving the therapeutic window. The valine citrulline monomethyl auristatin E (vcMMAE, conventional linker-drug) ADC platform has shown promising clinical activity in several cancers, but peripheral neuropathy (PN) is a frequent adverse event leading to treatment discontinuation and dose reduction. This was not predicted based on nonclinical toxicology studies in monkeys or rats treated with vcMMAE ADCs. We evaluated four hypotheses for the lack of translatability of PN with vcMMAE ADCs: 1) species differences in exposure; 2) insensitivity of animal models; 3) species differences in target biology and other vcMMAE ADC properties in peripheral nerves and 4) increased susceptibility of patient population. The result of this hypothesis-based approach identified opportunities to improve the predictivity of PN in our animal models by increasing duration of exposure and adding an expanded neurohistopathology assessment of peripheral nerves. The utility of a predictive animal model would be to provide possible mitigation strategies in the clinic with vcMMAE ADCs and help to screen the next generation microtubule inhibitor (MTI) ADCs for reduced PN.


Assuntos
Anticorpos/toxicidade , Antineoplásicos/toxicidade , Imunoconjugados/toxicidade , Oligopeptídeos/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Testes de Toxicidade/métodos , Pesquisa Médica Translacional/métodos , Moduladores de Tubulina/toxicidade , Animais , Anticorpos/química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Composição de Medicamentos , Interações Medicamentosas , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Modelos Animais , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Farmacogenética , Medição de Risco , Especificidade da Espécie , Fatores de Tempo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinética
17.
MAbs ; 8(8): 1612-1619, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27653831

RESUMO

DSTA4637A, a novel THIOMAB™ antibody antibiotic conjugate (TAC) against Staphylococcus aureus (S. aureus), is currently being investigated as a potential therapy against S. aureus infections. Structurally, TAC is composed of an anti-S. aureus antibody linked to a potent antibiotic, dmDNA31. The goal of the current study was to characterize the pharmacokinetics (PK) of TAC in mice, assess the effect of S. aureus infection on its PK, and evaluate its pharmacodynamics (PD) by measuring the bacterial load in various organs at different timepoints following TAC treatment. Plasma concentrations of 3 analytes, total antibody (TAb), antibody-conjugated dmDNA31 (ac-dmDNA31), and unconjugated dmDNA31, were measured in these studies. In non-infected mice (target antigen absent), following intravenous (IV) administration of a single dose of TAC, systemic concentration-time profiles of both TAb and ac-dmDNA31 were bi-exponential and characterized by a short distribution phase and a long elimination phase as expected for a monoclonal antibody-based therapeutic. Systemic exposures of both TAb and ac-dmDNA31 were dose proportional over the dose range tested (5 to 50 mg/kg). In a mouse model of systemic S. aureus infection (target antigen present), a single IV dose of TAC demonstrated PK behavior similar to that in the non-infected mice, and substantially reduced bacterial load in the heart, kidney, and bones on 7 and 14 d post dosing. These findings have increased our understanding of the PK and PK/PD of this novel molecule, and have shown that at efficacious dose levels the presence of S. aureus infection had minimal effect on TAC PK.


Assuntos
Antibacterianos/farmacocinética , Anticorpos Antibacterianos/farmacologia , Anticorpos Monoclonais/farmacocinética , Imunoconjugados/farmacocinética , Infecções Estafilocócicas/tratamento farmacológico , Animais , Camundongos , Staphylococcus aureus
18.
MAbs ; 8(5): 991-7, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27031797

RESUMO

MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Antivirais/farmacologia , Influenza Humana/tratamento farmacológico , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Teóricos
19.
Biopharm Drug Dispos ; 37(2): 66-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25904406

RESUMO

Antibody-drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and to minimize toxicity in patients. Significant progress has been made in recent years in this area, however, many fundamental questions still remain. This review discusses factors to consider while assessing the disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos/farmacocinética , Imunoconjugados/farmacocinética , Animais , Humanos
20.
Clin Cancer Res ; 22(6): 1469-79, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26589434

RESUMO

PURPOSE: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody. EXPERIMENTAL DESIGN: The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies. RESULTS: Anti-DLL4 F(ab')2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition. CONCLUSIONS: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans.


Assuntos
Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macaca fascicularis , Camundongos , Ratos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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