Lipid-engineered antibody-based therapeutics target inflamed joints and lymph nodes to enhance rheumatoid arthritis...

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint damage. Although antibody (Ab)-based biologic disease-modifying anti-rheumatic drugs (bDMARDs) have transformed RA treatment, their efficacy remains limited in many patients. Here, we conjugate Ab-based bDMARDs with pegylated diacyllipid (DP) motifs to enable their albumin hitchhiking after subcutaneous administration, thereby targeting these lipid-drug conjugates (LDCs) to both inflamed joints and lymph nodes (LNs) for enhanced and concurrent immunosuppression. Multivalent DP conjugation allows bDMARDs larger than albumin to engage multiple albumin molecules, further enhancing albumin-mediated targeting. In a collagen-induced arthritis model, DP modification substantially improves the therapeutic efficacy of two representative bDMARDs, TNF-α-neutralizing Ab (aTNF-α) and CTLA4-immunoglobin recombinant protein (CTLA4), without detectable additional safety risks. bDMARDs bearing two DP moieties significantly outperform their single-DP-modified counterparts, consistent with more extensive albumin engagement. LDC offers a potent, facile, and broadly applicable strategy for targeting Ab-based therapeutics to inflamed tissues and LNs.