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1.
Recent Results Cancer Res ; 214: 1-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473848

RESUMO

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunoterapia , Neoplasias/terapia , Ensaios Clínicos como Assunto , Humanos
2.
Biochem J ; 475(13): 2179-2190, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29794155

RESUMO

Antibody engineering is important for many diagnostic and clinical applications of monoclonal antibodies. We recently reported a series of fragment crystallizable (Fc) mutations targeting the neonatal Fc receptor (FcRn) site on a Lewis Y (Ley) binding IgG1, hu3S193. The hu3S193 variants displayed shortened in vivo half-lives and may have potential for radioimaging or radiotherapy of Ley-positive tumors. Here, we report Fc crystal structures of wild-type hu3S193, seven FcRn-binding site variants, and a variant lacking C1q binding or complement-dependent cytotoxicity (CDC) activity. The Fc conformation of the FcRn-binding sites was similar for wild-type and all mutants of hu3S193 Fc, which suggests that FcRn interactions were directly affected by the amino acid substitutions. The C1q-binding site mutant Fc was nearly identical with the wild-type Fc. Surprisingly, several hu3S193 Fc variants showed large changes in global structure compared with wild-type Fc. All hu3S193 Fc mutants had similar antibody-dependent cellular cytotoxicity, despite some with conformations expected to diminish Fc gamma receptor binding. Several hu3S193 variants displayed altered CDC, but there was no correlation with the different Fc conformations. All versions of hu3S193, except the C1q-binding site mutant, bound C1q, suggesting that the altered CDC of some variants could result from different propensities to form IgG hexamers after engaging Ley on target cells. Overall, our findings support the concept that the antibody Fc is both flexible and mobile in solution. Structure-based design approaches should take into account the conformational plasticity of the Fc when engineering antibodies with optimal effector properties.

3.
MAbs ; 8(4): 775-86, 2016 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27030023

RESUMO

IgG has a long half-life through engagement of its Fc region with the neonatal Fc receptor (FcRn). The FcRn binding site on IgG1 has been shown to contain I253 and H310 in the CH2 domain and H435 in the CH3 domain. Altering the half-life of IgG has been pursued with the aim to prolong or reduce the half-life of therapeutic IgGs. More recent studies have shown that IgGs bind differently to mouse and human FcRn. In this study we characterize a set of hu3S193 IgG1 variants with mutations in the FcRn binding site. A double mutation in the binding site is necessary to abrogate binding to murine FcRn, whereas a single mutation in the FcRn binding site is sufficient to no longer detect binding to human FcRn and create hu3S193 IgG1 variants with a half-life similar to previously studied hu3S193 F(ab')2 (t1/2ß, I253A, 12.23 h; H310A, 12.94; H435A, 12.57; F(ab')2, 12.6 h). Alanine substitutions in S254 in the CH2 domain and Y436 in the CH3 domain showed reduced binding in vitro to human FcRn and reduced elimination half-lives in huFcRn transgenic mice (t1/2ß, S254A, 37.43 h; Y436A, 39.53 h; wild-type, 83.15 h). These variants had minimal effect on half-life in BALB/c nu/nu mice (t1/2ß, S254A, 119.9 h; Y436A, 162.1 h; wild-type, 163.1 h). These results provide insight into the interaction of human Fc by human FcRn, and are important for antibody-based therapeutics with optimal pharmacokinetics for payload strategies used in the clinic.


Assuntos
Anticorpos Monoclonais/química , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoglobulina G/química , Receptores Fc/química , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Meia-Vida , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Sistema do Grupo Sanguíneo de Lewis/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Engenharia de Proteínas , Estabilidade Proteica , Receptores Fc/imunologia
4.
Pharm Res ; 30(12): 3238-53, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24092054

RESUMO

PURPOSE: Little is known about the microstructure of lipid-based formulations, or how their structure changes as they disperse in the lumen of the gastrointestinal tract. We used molecular dynamics (MD) simulation to study such formulations at the molecular level as they interact with water during dispersion. METHODS: We studied a simple lipid formulation, by itself and in the presence of drugs. The formulation contained mono- and di-lauroyl glycerides at 0-75% (w)/w water. Acyclovir, danazol, hydrocortisone, ketoprofen or progesterone, were included to investigate their dynamic behavior and localization during dispersion. RESULTS: Micro-structuring of the formulation was evident at all water concentrations. As the water content increased, the microstructure evolved from a continuous phase containing isolated water molecules, to a reverse micellar solution and finally to a system containing lamellar lipids with large pools of free water. Drugs partitioned into the aqueous and lipid domains principally under the influence of hydrogen bonding and hydrophobic interactions. Drugs located preferentially to the interfaces between water and lipid where they are able to make both hydrophobic and hydrophilic interactions. CONCLUSION: Molecular dynamics simulations offer an unprecedented view of the structure of lipid-based formulations and has considerable potential as an in silico tool for formulators.


Assuntos
Excipientes/química , Glicerídeos/química , Lipídeos/química , Preparações Farmacêuticas/química , Simulação de Dinâmica Molecular , Transição de Fase , Solubilidade
5.
Langmuir ; 27(18): 11381-93, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21838286

RESUMO

The prediction of surfactant phase behavior has applications in a wide range of areas. An accurate modeling of liquid phase behavior can aid our understanding of colloidal process or be used to design phases that respond in a defined way to their environment. In this work, we use molecular dynamics to model the phase behavior of the ternary sodium laurate/sodium oleate/water system and compare the simulation results to experimental data. Simulations were performed with the GROMOS 53A6 united-atom force field and cover the entire ternary phase diagram, producing micellar, hexagonal, and lamellar phases. The aggregate simulation time for the 33 simulations performed during this study is 4.4 µs. We find that the simulations were able to model the experimentally observed liquid phase behavior accurately, showing that the carboxylate and lipid parameters of the 53A6 force field give very good quality results for the in silico prediction of liquid system phase behavior.


Assuntos
Ácidos Láuricos/química , Simulação de Dinâmica Molecular , Ácido Oleico/química , Água/química , Líquidos Iônicos/química , Conformação Molecular , Óleos/química
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