Antibodies improved pharmacokinetics

By using recombinant DNA techniques, modifications in the protein backbone, such as additions, deletions and alterations of amino acids, are easily achieved. These modifications can contribute to improved pharmacokinetic properties of the construct. Additions may consist of the introduction of residues that allow covalent conjugation of drug molecules. Deletions of amino acids can employed to remove membrane-bound regions of a protein, thereby increasing its solubility. Single amino acid modifications can be used to minimize antibody responses and alter the binding specificity and/or the three-dimensional structure of a certain protein. 

Walsh, S., A. Shah, and J. Mond. 2003. Improved pharmacokinetics and reduced antibody reactivity of lysostaphin conjugated to polyethylene glycol. Antimicrob. Agents Chemother. 47 554—558. 

Parenteral administration (injection), which is the immediate option for orally undeliverable drugs, has advanced greatly in recent years for systemic and local drug delivery. " The novel drug delivery system has metamorphosed from simple polymer and antibody conjugates to sterically stabilized colloidal systems. Liposomes and nanoparticles can improve pharmacokinetic-pharmacody-... 

Genetic engineering advances in improving the selectivity of therapeutic monoclonal antibodies (mAbs) in terms of their improved pharmacokinetics, binding affinities, specificities, toxicides, and increased half-life. 

Kletting, R, KuU, T, Bunjes, D., Mahren, B., Luster, M., Reske, S. N. and Glatting, G. 2010. Radioimmunotherapy with anti-CD66 antibody Improving the biodistribution using a ph) iologically based pharmacokinetic model / Nucl Med, 51,484-91. 

The structural submodel describes the central tendency of the time course of the antibody concentrations as a function of the estimated typical pharmacokinetic parameters and independent variables such as the dosing regimen and time. As described in Section 3.9.3, mAbs exhibit several parallel elimination pathways. A population structural submodel to mechanistically cover these aspects is depicted schematically in Fig. 3.14. The principal element in this more sophisticated model is the incorporation of a second elimination pathway as a nonlinear process (Michaelis-Menten kinetics) into the structural model with the additional parameters Vmax, the maximum elimination rate, and km, the concentration at which the elimination rate is 50% of the maximum value. The addition of this second nonlinear elimination process from the peripheral compartment to the linear clearance process usually significantly improves the fit of the model to the data. Total clearance is the sum of both clearance parts. The dependence of total clearance on mAb concentrations is illustrated in Fig. 3.15, using population estimates of the linear (CLl) and nonlinear clearance (CLnl) components. At low concentra-... 

The first and the second approaches have provided some positive results but, unfortunately, they depend upon the structure of the protein. Typical examples of sequence modifications to improve stability and pharmacokinetics are the preparation of humanized antibodies, where part of the mouse sequence is substituted by the human form, and the granulocyte colony-stimulating factor muteins, where up to seven amino acids are substituted. Examples of truncated sequence proteins with improved characteristic are the 7-36 analogues of glucagon-like peptides or the 1-29 sequence growth hormone-releasing factor [1, 2]. 

Suppression of immunogenicity by PEGylation is primarily based on shielding of the epitope (immunoreactive site) of a protein by flexible PEG chains. Improved immunological properties alter the pharmacokinetic profile of the modified protein. For example, when IgG was intravenously administrated to monkeys, it was cleared rapidly because of an antiprotein immune response [52]. On the other hand, PEGylated IgG did not elicit an immune response, and their dose levels were 125% as compared with the native antibody. This indicated that PEGylation of a protein increases the circulation time in the bloodstream by reducing clearance by the immune system. 

As the site on IgG that is responsible for binding to FcRn has been mapped and well characterized, the trend in the field of antibody engineering is to mutate the FcRn-binding site. Therefore, an increased FcRn binding provides altering the pharmacokinetics of mAbs. In 2002, Dall Acqua et al. found that major improvement in FcRn binding occurred when mutations were introduced at positions 252,... 

TNF-a Patients with RA Adalimumab (a human anti-TNF a monoclonal antibody) added to continuing MTX therapy Coadministration of adalimumab and MTX Adalimumab exhibited linear pharmacokinetics. Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved long-term improvement compared with placebo plus MTX [12]... 

Fig. 5 Schematic diagram of the siRNA delivery system. A cationic group is universal in all siRNA delivery systems to condense siRNA into nanosized complex. To release the siRNA from the endosome after endocytosis, an endosomal disrupting agent is also essential. PEG modification is also important to improve the pharmacokinetic profile of the complex, as well as to avoid the nonspecific uptake by RES. To achieve the targeted delivery to tumor cells, various ligands including antibody, antibody fragments, peptides, small molecules should be modified to the complex directly or via PEG as a linker...

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