Sandbox Reserved 1474: Difference between revisions
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IgG mAbs are typically chimeric, humanized, or fully human proteins. The longest t1/2lamdaz values are usually achieved when the antibody does not bind to tissue sites and is not prematurely cleared due to antigenicity. | IgG mAbs are typically chimeric, humanized, or fully human proteins. The longest t1/2lamdaz values are usually achieved when the antibody does not bind to tissue sites and is not prematurely cleared due to antigenicity. | ||
Ch-mAb7F9, a chimeric mAb is produced as a treatment medication for METH abuse. In vitro, it is shown only binds to (+)METH (KD=6.9nM), (+)AMP( | Ch-mAb7F9, a chimeric mAb is produced as a treatment medication for METH abuse based on the murine anti-METH mAb7F9. It is created by preserving mAb7f9 variable region with human IgG2 constant domains to minimize the risk of effector function. In vitro, it is shown only binds to (+)METH (KD=6.9nM), (+)AMP(KI = 350 nM), (+)MDMA(kI=6.7nM). | ||
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====Cross reactions in vitro ligand binding studies==== | |||
It did not bind endogenous neurotransmitters or other medications and was not bound by protein C1q, result of the test that was conducted to determine the potential for complement activation, which is an undesired effector function, thus it is unlikely to stimulate in vivo complement-dependent cytotoxicity. <ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" /> | |||
Just as mAb7F9, ch-mAb counterpart does not bind any of these compounds except (+)AMP, (+)METH and (+)MDMA well enough to raise clinical effect and in vitro with only one interesting exception: (-)MDMA, which was capable of inhibiting [3H]METH binding at greater than 50% and it was the only ligand with a KI (ocncentration of inhibitor that prevents 50% of the [H3] from binding) less than 1 microMolar among other tested compounds. However, due to Ecstasy is a racemic mixture contains both (+) and (-) MDMA and the ability that mAb7F9 to bind both forms of MDMA may actually improve its utility as a potential treatment for MDMA abuse. | |||
<table><tr><td colspan='2'>Table 2 <ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" />Ligands tested in Ch-mAb7F9 cross-reactivity study.<br></td></tr> | |||
Table 2 <ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" / | |||
<tr id='Related stimulates'><td class="sblockLbl"><b>Related stimulates</b></td><td class="sblockDat"> | <tr id='Related stimulates'><td class="sblockLbl"><b>Related stimulates</b></td><td class="sblockDat"> | ||
(+)-Methamphetamine, | (+)-Methamphetamine, | ||
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====Isothermal titration calorimetry potency studies==== | ====Isothermal titration calorimetry potency studies==== | ||
Isothermal titration calorimetry analysis of ch-mAb7F9 binding to METH provided thermodynamic and stoichiometry measurements.<ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" /> | Isothermal titration calorimetry analysis of ch-mAb7F9 binding to METH provided thermodynamic and stoichiometry measurements for its potency.<ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" /> | ||
<table><tr><td colspan='2'> Antibody thermodynamic values and stoichiometry for target binding<ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" />.<br></td></tr> | <table><tr><td colspan='2'> Antibody thermodynamic values and stoichiometry for target binding<ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" />.<br></td></tr> | ||
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</table> | </table> | ||
The gibbs free energy change is very similar to other antibodies reported in study. Like others, binding is mostly driven by a favorable enthalpy change that compensates for an almost nonexistent entropy penalty. The stoichiometry is expected to be 2 binding sites per antibody molecule and it is almost completely active. | |||
====Pharmacokinetics studies in rats==== | |||
METH had little effect on ch-mAb7F9 disposition, ch-mAb7F9 substantially altered METH disposition. Both in vitro and in vivo demonstrated ch-mAb7F9 is pharmacologically similar to its murine counter part<ref name="Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use" /> | |||
In the current studies, a t1/2lamdaZ of 10-13 days for ch-mAb7F9 in rats was observed. The half life is predicted to be 3 weeks in human roughly 3 folds of that of rat due to the Vdss of IgG in both species is similar yet the ClT in humans is one third of that in rats. | |||
== Human Study == | == Human Study == | ||
