Humanized Anti-IgE monoclonal antibody(Tianchen Biomedical)

Autosomal dominant signal transducer and activator of transcription 3 (STAT3) mutations are broadly classified into loss-of-function (LOF) and gain-of-function (GOF) variants. LOF mutations in STAT3 are responsible for autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES), a rare primary immunodeficiency disorder. This condition is characterized by elevated serum immunoglobulin E (IgE) levels, chronic eczema, and recurrent respiratory tract infections. Current conventional management strategies include antimicrobial therapy, immunoglobulin replacement, and systematic airway clearance. However, there remains a lack of targeted therapies specifically for AD-HIES, leading to substantial morbidity and significantly compromised quality of life for affected patients. Omalizumab, a monoclonal anti-human IgE antibody, is approved for the treatment of asthma and chronic spontaneous urticaria, but is rarely used in AD-HIES. Relevant studies on the application of omalizumab in AD-HIES patients primarily focus on alleviating skin issues, with significant improvements reported in most cases, but rarely focus on alleviating the lung symptom. We report two cases in which both skin and lung symptoms improved through a combination of omalizumab and conventional treatment.

We report two cases of AD-HIES caused by STAT3 mutations, both complicated by pulmonary involvement. These two patients continued to experience frequent acute infections despite long-term antibiotic use, regular airway clearance, and other conventional treatments. We introduced omalizumab as an adjunct to their existing therapy. After 9 months of treatment, both their skin and lung symptoms were well controlled. The administration of omalizumab in combination with conventional therapy resulted in varying degrees of clinical improvement.

The combination of omalizumab with conventional therapy may contribute to improved pulmonary and dermatological symptoms in patients with AD-HIES resulting from STAT3 LOF mutations.

PRO 140, a humanized anti-HIV monoclonal antibody targeting the cell coreceptor CCR5, is currently under clinical trials, but it only affects CCR5-tropic viruses. In this study, we have engineered two tandem fusion proteins (2P23-PRO140SC and 2P23-PRO140-Fc) with bifunctional activity by adding short fusion-inhibitory peptide 2P23 to the single-chain fragment variable (scFv) of PRO 140 (PRO140SC) with or without the Fc domain of human IgG4. We first demonstrated that 2P23-PRO140SC and 2P23-PRO140-Fc could efficiently bind to the cell membranes through CCR5 anchoring, which did not affect the expression level of CCR5 on the cell surface. We then verified that the addition of 2P23 peptide to PRO140SC enabled a very potent activity against CXCR4-tropic HIV-1 isolates. As expected, the bispecific fusion proteins exhibited highly potent activities in inhibiting divergent HIV-1 subtypes and viral mutants that were resistant to the fusion inhibitors 2P23 and T20, and they displayed relatively low in vitro cytotoxicity. Furthermore, both the fusion proteins had robust in vivo anti-HIV activities in rats, with 2P23-PRO140-Fc much better than 2P23-PRO140SC. In conclusion, our studies have provided bispecific HIV-1 inhibitors that overcome the drawbacks of PRO 140 antibody and offered novel tools for studying the mechanisms of HIV-1 infection.

Given that HIV-1 evolves with high variability and drug resistance, the development of novel antivirals is important. CCR5-directed antibody PRO 140 is currently under clinical trials, but it only inhibits CCR5-tropic HIV-1 isolates. The designed fusion proteins by adding a minimum fusion-inhibitory peptide to PRO 140 enable dramatically increased activities in inhibiting both CCR5-tropic and CXCR4-tropic viruses, thus offering novel antiviral agents with a bispecific functionality that can overcome the drawbacks of PRO 140 antibody.