Tumor necrosis factor antagonist mechanisms of action: A comprehensive review

Antibodies constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The generation of potent antibody therapeutics, which I review here, is an iterative design process that involves the generation and optimization of antibodies to improve their clinical potential.

Potent antibody therapeutics by design

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/jps.20727

Antibody structure, instability, and formulation

The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.

Therapeutic antibodies for autoimmunity and inflammation

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease.

Dual variable domain immunoglobulins and uses thereof

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.20178

Antibody pharmacokinetics and pharmacodynamics.

The time course of chemotherapeutic effect is often delayed relative to the time course of chemotherapeutic exposure. In many cases, this delay is difficult to characterize mathematically through the use of standard pharmacodynamic models. In the present work, we investigated the relationship between methotrexate (MTX) exposure and the time course of MTX effects on tumor cell growth in culture. Two cancer cell lines, Ehrlich ascites cells and sarcoma 180 cells, were exposed for 24 hours to MTX concentrations that varied more than 700-fold (0.19–140 μg/mL). Viable cells were counted on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 20, 22, and 24 for Ehrlich ascites cells and on days 1, 2, 3, 5, 7, 9, 11, 13, 14, 15, 17, 19, and 21 for sarcoma 180 cells, through the use of a tetrazolium assay. Although MTX was removed 24 hours after application, cell numbers reached nadir values more than 100 hours after MTX exposure. Data from each cell line were fitted to 3 pharmacodynamic models of chemotherapeutic cell killing: a cell cycle phase-specific model, a phase-nonspecific model, and a transit compartment model (based on the general model recently reported by Mager and Jusko, Clin Pharmacol Ther. 70:210–216, 2001). The transit compartment model captured the data much more accurately than the standard pharmacodynamic models, with correlation coefficients ranging from 0.86 to 0.999. This report shows the successful application of a transit compartment model for characterization of the complex time course of chemotherapeutic effects; such models may be very useful in the development of optimization strategies for cancer chemotherapy.

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Pharmacodynamic modeling of chemotherapeutic effects: application of a transit compartment model to characterize methotrexate effects in vitro.

Pharmacokinetic–pharmacodynamic modeling of methotrexate‐induced toxicity in mice

Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice.

Highly sensitive high-performance liquid chromatographic assay for methotrexate in the presence and absence of anti-methotrexate antibody fragments in rat and mouse plasma.

Evelyn D. Lobo

Papers

Antibody pharmacokinetics and pharmacodynamics.

Pharmacodynamic modeling of chemotherapeutic effects: application of a transit compartment model to characterize methotrexate effects in vitro.

Pharmacokinetic–pharmacodynamic modeling of methotrexate‐induced toxicity in mice

Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice.

Highly sensitive high-performance liquid chromatographic assay for methotrexate in the presence and absence of anti-methotrexate antibody fragments in rat and mouse plasma.