Spatial‐hindrance‐based pro‐Adalimumab prevents anti‐idiotypic antibody interference in pharmacokinetic and therapeutic efficacy

Abstract

Adalimumab (Humira) represents a major advance in rheumatoid arthritis (RA) therapy. However, with long‐term administration of Adalimumab, anti‐idiotypic antibody (anti‐Id Ab) accelerates the Adalimumab clearance rate and reduces the therapeutic effect. To avoid the interference of anti‐Id Ab, we used an autologous hinge region as a spatial‐hindrance‐based Ab lock and connected it to the N‐terminal of the light chain and heavy chain via substrate peptides (MMP‐2/9) to cover the CDR binding site of Adalimumab to generate pro‐Adalimumab. The Ab lock masks the complementarity‐determining regions (CDRs) of Adalimumab, thus avoiding interference from anti‐Id Ab. Pro‐Adalimumab demonstrated a 241.6 times weaker binding ability to TNFɑ than Adalimumab. In addition, pro‐Adalimumab showed a 46.6‐fold greater blocking of anti‐Adalimumab Id Ab in comparison to Adalimumab prior to activation. Similar results were observed with other clinical antibodies, such as pro‐Infliximab (anti‐TNFɑ Ab) and pro‐Nivolumab (anti‐PD‐1). Furthermore, pro‐Adalimumab maintained consistent pharmacokinetics regardless of the presence of anti‐Adalimumab Id antibodies, while Adalimumab showed a 49% clearance increase, resulting in a near complete loss of function. Additionally, pro‐Adalimumab was able to avoid neutralization and efficiently reduce RA progression in the presence of anti‐Adalimumab Id Ab in vivo. In summary, we developed a pro‐Adalimumab that avoids interference from anti‐Id Abs, thereby addressing the biggest issue limiting clinical efficacy. The findings enclosed herein may have potentially broad application in antibody therapies.