InVivoMAb recombinant human IgG1 Fc

Interleukin-2 (IL-2) is a cytokine with curative potential in cancer immunotherapy, but its clinical use is limited by a narrow therapeutic window. Traditional strategies such as polarizing receptor binding or fusing IL-2 with Fc (IL-2-Fc) improve pharmacokinetics and immune selectivity, but systemic toxicity remains a key challenge, while covalent prodrug designs may compromise potency and restrict applicability. Here, we present a non-covalent approach using clinically validated ultra pH-sensitive (UPS) polymers to enable tumor-specific IL-2 activation. The UPS5.3/IL-2-Fc nanoparticle remains stable at physiological pH, minimizing receptor binding in normal tissues, but dissociates and restores IL-2 activity in severely acidic tumor environments (pH < 5.3). This pH-triggered activation reduces systemic toxicity, resulting in over 100-fold reduction in circulating interferon-γ and prevention of vascular leak syndrome, while preserving antitumor efficacy. Mechanistically, the protective effect relies on both pH-dependent shielding and macrophage clearance. This bioengineering strategy offers a generalizable framework for immune cytokine therapy.

Rheumatoid arthritis (RA) is a common systemic autoimmune disorder. Fibroblast-like synoviocytes (FLS) have emerged as an attractive target for nonimmunosuppressive RA therapy, but there are no approved drugs targeting FLS. The receptor protein tyrosine phosphatase sigma (PTPRS) negatively regulates FLS migration and has been proposed as a target for FLS-directed RA therapy. Here we examined the impact of sequence variations on efficacy of an FLS-targeted biologic composed of Fc-fused PTPRS IgG-like domains Ig1 and Ig2 (Ig1&2-Fc). Engineering the linker and Fc tag improved effectiveness of human Ig1&2-Fc in assays of FLS migration and a mouse model of arthritis. Treatment of mice with Ig1&2-Fc over 4 months revealed no signs of toxicity or organ pathology. Finally, we show potential of Ig1&2-Fc coadministration in combination or as a bispecific fusion with a tumor necrosis factor-α inhibitor. Combination treatment of mouse tumor necrosis factor receptor 2 (mTnfr2) with Ig1&2-Fc resulted in increased efficacy in suppressing arthritis beyond single-agent treatment. When administered as a dual-action bispecific, Ig1&2 fused to mTnfr2 proved more efficacious at suppressing arthritis than mTnfr2 alone. This study illustrates the potential of Ig1&2-Fc as a combination or bispecific therapy with disease-modifying antirheumatic drugs to improve patient outcomes in RA.

Pain is a key symptom associated with rheumatoid arthritis (RA) and can persist even in the context of overall disease control by standard-of-care disease modifying anti-rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for pain relief but lack disease modifying properties, and their sustained use carries adverse risks. In this work, we characterized the progression of pain sensitivity in the SKG mouse model of RA and evaluated the potential therapeutic interventions. Male and female SKG mice, after systemic mannan injection, developed a mechanical pain phenotype and joint swelling, with a strong inverse correlation between clinical arthritis scores and pain thresholds. To test potential interventions for pain alleviation, we evaluated all-trans retinoic acid (ATRA)-loaded poly(lactic-co-glycolic acid) microparticles (ATRA-PLGA MP) administered via intra-articular injection, which we have previously demonstrated to be disease-modifying. The pain and inflammation patterns assessed by the von Frey test and clinical scoring showed ATRA-PLGA MP monotherapy reduced inflammation and alleviated mechanical allodynia in arthritic SKG mice, an effect that was amplified by combination treatments with standard-of-care agents. In early-stage arthritis, co-administration with cytotoxic T-lymphocyte-associated protein (CTLA)-4-Ig, clinically known as abatacept, delayed disease progression and sustained the reduction of mechanical allodynia. In established arthritis, sequential treatment with the corticosteroid dexamethasone (Dex) reduced cumulative disease burden and reduced mechanical allodynia. These findings highlight the potential of combining ATRA-PLGA MP with standard-of-care treatments as a potential strategy to enhance the efficacy and durability of disease modification and pain alleviation for arthritis management.

Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.