Abstract
During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.
Highlights
Antitumor necrosis factor α antibodies constitute a major advance in rheumatoid arthritis (RA) therapy in the clinic, as targeting TNFα in the disease region can reduce pathological inflammation and efficiently inhibit RA progression [1]
The results demonstrated that matrix metalloproteinase (MMP)-2/9 could completely remove the antibody lock” (Ab lock) from pro-Infliximab (S1 Fig), and the TNFα-binding ability of pro-Infliximab was gradually elevated in a time-dependent manner during MMP-2/9 treatment (S2 Fig)
We believe that the MMP-cleavable and efficient Ab lock can significantly increase the selective reaction of Infliximab at the disease site and reduce the on-target toxicities of Infliximab during systemic circulation, thereby showing potential to improve the quality of life of RA patients
Summary
Antitumor necrosis factor α antibodies (anti-TNFα Abs) constitute a major advance in rheumatoid arthritis (RA) therapy in the clinic, as targeting TNFα in the disease region can reduce pathological inflammation and efficiently inhibit RA progression [1]. In addition to their biological importance, anti-TNF biologics constitute the most profitable drug class in history, exceeding US$25 billion total sales globally [2]. Singh and colleagues indicated the risk of serious infections is increased 30% during the treatment of anti-TNFα therapy [11], and common infections such as tuberculosis (TB), bacterial sepsis, Streptococcus pneumoniae, and Listeria monocytogenes might lead to hospitalization or death. There is an urgent need to solve the on-target toxicities that accompany anti-TNFα therapy to provide higher selectivity and a safe treatment for RA patients
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