1729: An Antibody-drug Conjugate of Anti-TNFα Antibody and a Novel Glucocorticoid Molecule Exerts Synergistic Anti-inflammatory Effects for Treatment of Autoimmune Diseases

Yuhao Qin¹, Wenming Ren², Liangqin Tong³, lu su³ and cheng liao³, ¹Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China, ²Jiangsu Hengrui Pharmaceuticals Co., Ltd., Pudong New District, China, ³Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

Background/Purpose: Tumor necrosis factor α (TNFα) is a pivotal pro-inflammatory cytokine. And TNF inhibitors are the most successful anti-rheumatic drugs for the treatment of autoimmune diseases such as rheumatic arthritis. However, many patients respond poorly or lose response gradually to anti-TNF therapies. Glucocorticoids (GCs), which exert extensive immunosuppressive effects by inhibiting the nuclear factor kappa-B signaling pathway, have been the most powerful and basic/standard treatment for many autoimmune diseases, while their long-term usage is strictly limited due to the adverse effects. Here, we describe the preclinical characterization of an anti-TNF conjugate which is consisted of an anti-TNFα antibody and a novel GC molecule with high potency.

Methods: The glucocorticoid receptor (GR) binding activity of the GC molecule was measured in a GR biochemical assay. The binding affinity of the anti-TNF conjugate with TNFα were assessed by surface plasmon resonance assay. The TNF inhibitory activities of the anti-TNF conjugate were evaluated in LPS-induced monocyte IL-6 release assay and TNFα-induced L929 cytotoxicity assay. And the in vivo efficacy of the anti-TNF conjugate was determined in dinitrofluorobenzene-induced delayed-type hypersensitivity (DTH) mouse model and the collagen antibody-induced arthritis (CAIA) mouse model. In addition, a 4-week GLP repeated-dose toxicity study in cynomolgus monkeys was conducted to evaluate the safety profiles.

Results: The novel GC molecule was a high potent short-acting glucocorticoid. And the anti-TNF conjugate showed similar TNFα binding affinity and TNFα-induced cytotoxic inhibitory activity to the anti-TNFα antibody. The anti-TNF conjugate could block the pro-inflammatory pathways by neutralizing soluble TNFα, and deliver the GC molecule specifically to pathogenic immune cells by binding to the transmembrane TNFα, which exerts synergistic anti-inflammatory effects and reduces the systemic exposure and side effects of GC. We proved that the anti-TNF conjugate inhibited LPS-induced IL-6 secretion in monocytes more potently than the anti-TNFα antibody. In DTH mouse model, the anti-TNF conjugate demonstrated better ear swelling remission than anti-TNFα antibody. In hTNFα-transgenic CAIA mice model, the disease severity score and histopathology were also significantly improved at a relatively low dose of the anti-TNF conjugate. Furthermore, the GLP repeated-dose toxicity study in cynomolgus monkeys showed the anti-TNF conjugate was well tolerated and no changes in cortisol were observed at doses up to 50 mg/kg. Our results showed the anti-TNF conjugate has a better efficacy than anti-TNFα antibody and has superiority in safety and tolerance compared to GCs.

Conclusion: Our data provides strong evidence that the anti-TNF conjugate is a potent anti-rheumatic drug with good safety profile, which support its further clinical application in autoimmune diseases including rheumatic arthritis and ulcerative enteritis.


Y. Qin: Jiangsu Hengrui Pharmaceuticals Co., Ltd., 3; W. Ren: Jiangsu Hengrui Pharmaceuticals Co., Ltd., 3; L. Tong: Jiangsu Hengrui Pharmaceuticals Co., Ltd., 3; l. su: Jiangsu Hengrui Pharmaceuticals Co., Ltd., 3; c. liao: Jiangsu Hengrui Pharmaceuticals Co., Ltd., 3.