Antibody Therapeutics最新文献

Backgroud: Nephrotic syndrome (NS) is a major cause of end-stage renal disease. Treating NS relies on immunosuppressants, which have numerous side effects. Therefore, there is an urgent need to identify effective and safe alternative treatments for NS. Angiopoietin-like protein 3 (ANGPTL3) exacerbates proteinuria, whereas interleukin (IL)-22 has a reparative effect on renal cells.

Methods: In the present study, we developed a bifunctional anti-ANGPTL3/IL-22 fusion protein and validated its efficacy in an adriamycin-induced nephropathy in mice.

Results: The fusion protein significantly decreased the urinary albumin-to-creatinine ratio, serum creatinine, blood urea nitrogen, and total cholesterol levels while increasing serum albumin levels. Pathological renal damage was also alleviated. These therapeutic effects were accompanied by the preservation of mitochondrial integrity, reduced apoptosis, and inhibited autophagy. Finally, we humanized the fusion protein to facilitate its potential clinical translation.

Conclusions: In conclusion, our results revealed that the anti-ANGPTL3/IL-22 bifunctional fusion protein ameliorates NS by protecting mitochondria, inhibiting apoptosis, and suppressing autophagy, highlighting a novel therapeutic approach for NS.

Background: As a clinical vaccine platform, lipid nanoparticle (LNP)-formulated mRNA has demonstrated potent and broad antibody responses, prompting speculation about its potential for antibody discovery. Membrane proteins remain among the most challenging targets for antibody development, highlighting the urgent need for technologies that preserve their native conformation during immunization and screening. Nanobodies (V_HHs), the single-domain fragments of heavy-chain-only antibodies naturally found in camelids, offer unique advantages over conventional antibodies, including high solubility, stability, and the ability to access cryptic or membrane-proximal epitopes.

Methods: Here, we report the first demonstration of target specific V_HH discovery in a llama using an mRNA-LNP immunization platform. A llama was immunized with LNPs encapsulating mRNA encoding the severe acute respiratory syndrome coronavirus 2 spike protein, a well-characterized model antigen. The resulting immune V_HH library was screened using a cell-based panning strategy that maintains antigen conformation and enables recovery of binders recognizing native epitopes.

Results: This approach yielded multiple high-affinity spike-specific V_HHs, including two clones that effectively blocked the spike-angiotensin-converting enzyme 2 interaction in a surrogate cell-based assay.

Conclusions: These findings demonstrate the feasibility of mRNA-LNP immunization as a rapid and efficient method for isolating target specific, functionally promising V_HHs from camelids. When combined with conformationally relevant screening, this platform may provide a versatile and accelerated route for generating high-quality V_HHs against complex or recalcitrant targets, particularly membrane proteins, thereby expanding the potential of V_HH-based therapeutics and diagnostics.

Monoclonal antibodies (mAbs), engineered to recognize disease-associated antigens, are central to cancer immunotherapy due to their ability to block or eliminate malignant cells by engaging immune effector mechanisms. Yet many tumors evade or suppress these responses, limiting durable clinical benefit and highlighting the need to optimize antibody-based strategies. A critical determinant of mAb activity is antibody isotype, which governs interactions with Fc receptors, complement pathways, and immune effector cells. While most approved therapeutics employ immunoglobulin G1 (IgG1) for its robust immune-stimulating capacity, evidence suggests that context-dependent isotype selection could improve efficacy. Here, we review the structural and functional properties of human IgG and IgA subclasses, with a focus on anti-CD20 rituximab in two- and three-dimensional models of human B-cell lymphoma. We further discuss how antigen density, tumor architecture, and host variables influence antibody-mediated effector functions. Together, these considerations highlight opportunities to refine antibody isotype selection for more individualized cancer immunotherapy.

Background: Cysteine-engineered monoclonal antibodies (mAbs), or ThiomAb, enable site-specific conjugation and form the basis of several next-generation antibody-drug conjugates (ADCs). However, the presence of intentionally unpaired cysteine residues introduces reactive free thiols that pose challenges for manufacturing consistency, including variable capping by cysteine/glutathione or uncapped free thiol during cell culture. This increases the charge heterogeneity of protein and may compromise stability due to increased risk of oxidation, disulfide scrambling, or aggregation.

Methods: To address these risks, we developed an on-column capping strategy, in which the antibody is immobilized on chromatography resin during the capture step and subjected to selective thiol masking under optimized redox conditions. This in-process approach allows for early and efficient stabilization of engineered thiol sites prior to polishing and formulation. High-throughput condition screening and analytical techniques-including mass spectrometry and charge variant profiling-were employed to fine-tune buffer conditions and understand on-column redox chemistry.

Results: The optimized thiol protection conditions substantially reduce the population of free thiols, resulting in more consistent charge profiles and improved stability during downstream processing and storage.

Conclusion: This strategy offers a scalable and platform-adaptable solution for enhancing the manufacturability and alternative control strategy of ThiomAb intermediates used in site-specific ADC processes.

Antibody-drug conjugates (ADCs) are a rapidly growing class of targeted therapeutics designed to deliver potent payloads while minimizing systemic toxicity. Despite significant progress, all approved ADCs are administered intravenously (IV). In contrast, subcutaneous (SC) delivery is well established for antibodies, offering shorter administration time, improved convenience, and the potential for outpatient or home-based treatment. Extending SC delivery to ADCs is therefore attractive but introduces unique challenges related to structural complexity, linker-payload instability, and cytotoxic payloads. This review evaluates the feasibility of subcutaneously administered ADCs by integrating insights from pharmacokinetic and pharmacodynamic studies, emerging clinical data, and advances in molecular design, formulation, and delivery technologies. Key challenges include limited clinical comparisons between IV and SC routes, uncertain bioavailability and tumor exposure, linker-payload instability, injection-site reactions, and high-concentration formulation constraints. Enabling strategies, such as rational molecular design, hyaluronidase-enabled delivery, polymer-based systems, and conversion of IV ADCs to SC dosing, are discussed. Recent advances, exemplified by JSKN033, demonstrate the feasibility of high-concentration liquid co-formulation approaches for SC administration and may represent a future direction. Evidence across oncology and non-oncology programs suggests that while SC delivery is achievable, success is highly molecule dependent. Overall, transitioning ADCs from IV to SC requires case-by-case evaluation and coordinated innovation across rational molecular design, formulation, and nonclinical and clinical development to realize the full patient-centric benefits of this approach.

Background: Helicobacter pylori infection is a global health concern associated with gastritis, peptic ulcer disease, and gastric cancer. With increasing antibiotic resistance, egg yolk immunoglobulin (IgY) has emerged as a promising candidate owing to its stability and pathogen-neutralizing effects. This clinical trial evaluated the efficacy of IgY-enriched egg yolk powder (anti-H. pylori IgY) in eliminating the bacterium and improving clinical symptoms as an adjunctive.

Methods: In this randomized, double-blind trial, 60 patients with confirmed H. pylori infection received a 14-day standard therapy regimen (omeprazole, amoxicillin, clarithromycin) supplemented with IgY-enriched egg yolk powder (intervention) or plain egg yolk powder (control). The primary outcome was bacterial eradication, assessed by the ¹⁴C-urea breath test performed 4 weeks after completion of therapy (i.e. 6 weeks from baseline). Secondary outcomes included symptom improvement (abdominal pain, nausea, bloating, and anorexia) measured using the Gastrointestinal Symptom Rating Scale, via telephone interviews conducted three times weekly for 3 weeks. Data were analyzed using analysis of variance and t-tests (SPSS v24).

Results: Baseline demographic characteristics were homogeneous. The median urea breath test value in the intervention group decreased from 77 to 11, whereas that of the control group remained unchanged (median = 55). Bacterial eradication was achieved in 33.3% of IgY recipients versus 13.3% of controls (difference, 20%; P = .241). IgY was well tolerated, with no treatment-related adverse events observed in the intervention group.

Conclusion: Clinical symptoms showed trends toward faster improvement, but these did not reach statistical significance. IgY may be a promising safe adjunct for the treatment of H. pylori infection.

Immune cell engagers have emerged as a powerful class of multi-specific therapeutics that redirect immune effector cells toward tumor cells to induce targeted cytotoxicity. Among these, T cell engagers (TCEs) represent the most clinically advanced platform, with multiple approved agents demonstrating substantial efficacy in hematologic malignancies. However, their broader application remains limited by systemic toxicities, antigen heterogeneity, and reduced efficacy in solid tumors. To address these challenges, next-generation TCEs are being engineered with improved selectivity, and optimized signaling properties. In parallel, increasing attention has shifted toward engaging alternative immune effectors, including γδ T cells, natural killer cells, and myeloid populations, which provide complementary mechanisms of tumor recognition and immune modulation. In this Review, we summarize the biological principles underlying T or other immune cell engagers, highlight emerging alternative platforms, and discuss evolving engineering strategies that are shaping the future of programmable cancer immunotherapy.

Therapeutic peptides have become an important class of pharmaceuticals, driven in part by the clinical success of long-acting incretin therapies. Despite their potency and specificity, peptides are intrinsically limited by rapid proteolytic degradation and renal clearance, resulting in short plasma half-lives and frequent dosing. Antibody-peptide conjugates represent an emerging class of biotherapeutics that combine the long half-life and target specificity of monoclonal antibodies (mAbs) with the chemical tunability and pharmacological activity of peptides. Unlike fusion proteins, antibody-peptide conjugates decouple peptide synthesis from antibody expression, enabling incorporation of non-proteinogenic amino acids, cyclic structures, and other chemical features that enhance peptide stability, potency, and half-life. This review examines the biological rationale, molecular design principles, and enabling technologies underlying antibody-peptide conjugates development, using the GIPR antagonist/GLP-1R agonist conjugate maridebart cafraglutide (AMG133) as a central case study. We illustrate how antibody-peptide conjugates can integrate complementary mechanisms of action into a single molecular entity and achieve sustained exposure profiles that are difficult to realize with fusion-based approaches. The discussion is extended to antibody-peptide conjugates programs across metabolic disease, oncology, neurology, pain, ocular, and infectious disease, highlighting recurring design themes such as half-life extension, targeted delivery, receptor-mediated internalization, and synergistic activity. Collectively, antibody-peptide conjugates represent a biology-driven and strategically important therapeutic modality that bridges antibody engineering and peptide medicinal chemistry. When guided by strong mechanistic rationale, antibody-peptide conjugates offer a powerful solution for therapeutic challenges that cannot be adequately addressed by peptides or antibodies alone.

In 2025, the 50th anniversary of the invention of hybridoma technology, the United States Food and Drug Administration (US FDA) approved a total of 44 new molecular entities (NMEs), of which 10 were therapeutic antibody-based molecules. Additionally, the US FDA approved 31 small molecules (of which one was a peptide), and 3 new nonantibody therapeutic proteins, but no new chimeric antigen receptor (CAR)-T-cell therapeutics. Of the new antibody-based biologics, two were antibody-drug conjugates, one was a T-cell engager-bispecific antibody, two were Fc-modified, half-life extended antibodies, and two targeted the complex coagulation pathway. The eighth novel anti-PD-1 antibody was also approved, along with the newest entry of biologics targeting the neonatal Fc receptor (FcRn). Additionally, two new entries in which hyaluronidase was coformulated with an antibody to provide rapid subcutaneous dosing were FDA-approved. Finally, the first antibody-like scaffold-fusion protein was approved that will compete in an antibody-rich environment.