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.

Keywords: Ab lock (hinge); avoid interference from anti‐id Abs; protease activation; pro‐adalimumab; rheumatoid arthritis.

FIGURE 1

Development of a spatial‐hindrance‐based Ab lock to prevent interference from anti‐Id Ab during Adalimumab treatment.

FIGURE 2

Ag‐binding and protease restoration through pro‐Adalimumab.

FIGURE 3

Comparison of the binding ability of anti‐Adalimumab Id Ab to pro‐Adalimumab and Adalimumab.

FIGURE 4

The Ag‐binding and protease‐restoration ability of pro‐Adalimumab in the presence of anti‐Adalimumab Id Ab.

FIGURE 5

The PK properties of pro‐Adalimumab in the presence of anti‐Adalimumab Id Ab.

FIGURE 6

The therapeutic efficacy of pro‐Adalimumab in human TNFɑ transgenic mice.