Comparison between a chimeric anti-methamphetamine monoclonal antibody and humanized antibodies on pharmacological...

Individuals with methamphetamine use disorder (MUD) can experience significant suffering due to the harmful effects of methamphetamine (METH) on physical and mental health. Although there are no approved medications for MUD, immunotherapies, including monoclonal antibodies (mAb), could serve as treatments for this debilitating condition. Our candidate anti-METH mAb called "devextinetug" features a mouse-derived variable binding region called "7F9" and a humanized constant domain. Our earlier work has shown that devextinetug is effective in altering METH's pharmacological effects. However, it is unknown whether the effectiveness of a chimeric mAb would be altered, or possibly improved, if the variable region were humanized. Moreover, no studies have determined whether onset and offset rates of binding to METH predicts anti-METH effectiveness of mAb candidates.

The goals of the present study were to compare the anti-METH effectiveness of a chimeric mAb (called "IS12") that features our parental 7F9 variable region with a panel of mAbs that have fully humanized variable regions, and to determine whether onset and/or offset rates of binding to METH are associated with anti-METH effectiveness.

We humanized the variable region from ch-mAb7F9 with multiple sequences to produce 48 IgGs. The on and off rates to METH binding were determined for these IgGs and, based on their various onset/offset rats, we chose eight candidate IgGs for further testing (including our parental IS12). All eight IgGs were tested for ligand cross-reactivity and in a METH-elicited locomotor stimulation model in rats.

Cross-reactivity results revealed that IS12 exhibited the greatest affinity to METH, and it also produced the largest reduction in METH-elicited locomotor stimulation compared to the other seven candidates. Furthermore, onset and offset rates of binding to METH did not appear to be associated with reducing METH's in vivo pharmacological effects.

The 7F9 variable region is the most promising to treat MUD.