Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-α antibody in a murine model of rheumatoid arthritis

BACKGROUND: Although disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model. METHODS: α-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2(123-144)). The binding activity of PlGF-2(123-144)-conjugated α-TNF (PlGF-2(123-144)-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2(123-144)-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse. RESULTS: PlGF-2(123-144) peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2(123-144)-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2(123-144)-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose. CONCLUSION: These data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.