Abstract

Cocaine abuse is a serious world‐wide health problem. No pharmacological agonist or antagonist of cocaine‐mediated CNS effects has yet been approved as a therapeutic to treat cocaine abuse relapse. However, human sequence monoclonal antibodies (mAb) that bind cocaine with high affinity and selectivity may provide an effective immunotherapy by blunting the addictive effects of cocaine in treated patients. Our laboratory has generated a mAb, designated 2E2, that meets several criteria for in vivo efficacy. Interestingly, 2E2 is composed of a human gamma heavy (H) and a murine lambda light (L) chain. Therefore, to further humanize 2E2's structure we have engineered a chimeric L chain consisting of the murine Lv variable domain and a human Lc constant region. Expression of the re‐engineered, recombinant mAb, denoted h2E2, in Chinese hamster ovary cells (CHO) and its physical characterization has been achieved. Binding studies indicate that h2E2 retains a high affinity (~4nM) and specificity for cocaine and cocaethylene. Studies determining and comparing the thermal and pH stability of h2E2 and its unfolding transitions as measured by differential scanning calorimetry to the parent 2E2 and other murine anti‐cocaine mAbs indicate that h2E2's stability is modestly improved. These results indicate that h2E2 is a suitable lead candidate therapeutic replacing mAb 2E2. Work supported by NIH grant 1DP1A031386.

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