Antibody Therapeutics最新文献

{"title":"Humanized anti-CD11d monoclonal antibodies suitable for basic research and therapeutic applications.","authors":"Eoin N Blythe, Christy Barreira, Corby Fink, Arthur Brown, Lynne C Weaver, Gregory A Dekaban","doi":"10.1093/abt/tbae031","DOIUrl":"10.1093/abt/tbae031","url":null,"abstract":"<p><strong>Background: </strong>Immunomodulatory agents targeting the CD11d/CD18 integrin are in development for the treatment of several pathophysiologies including neurotrauma, sepsis, and atherosclerosis. Murine anti-human CD11d therapeutic antibodies have successfully improved neurological and behavioral recovery in rodent neurotrauma models. Here, we present the progression of CD11d-targeted agents with the development of humanized anti-CD11d monoclonal antibodies.</p><p><strong>Methods: </strong>Primary human leukocytes and the THP-1 monocytic cell line were used to determine the binding of the CD11d antibodies, determine binding affinities, and assess outside-in signaling induced by CD11d antibody binding. In addition, a rat model of spinal cord injury was employed to demonstrate that the humanized monoclonal antibodies retained their therapeutic function <i>in vivo</i>. These determinations were made using a combination of flow cytometry, western blotting, immunohistochemistry, biochemical assays, and a locomotor behavioral assessment.</p><p><strong>Results: </strong>Flow cytometric analysis demonstrated that the humanized anti-CD11d clones bind both human monocytes and neutrophils. Using a THP-1 model, the humanized anti-CD11d-2 clone was then determined to bind both the active and inactive CD11d/CD18 conformations without inducing inflammatory cell signaling. Finally, an investigation using anti-CD11d-2 as a detection tool uncovered a mismatch between total and surface-level CD11d and CD18 expression that was not altered by CK2 inhibition.</p><p><strong>Conclusions: </strong>By developing humanized anti-CD11d monoclonal antibodies, new tools are now available to study CD11d biology and potentially treat inflammation arising from acute neurotrauma via CD11d targeting.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"8 1","pages":"26-39"},"PeriodicalIF":0.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical advice in the development of a lyophilized protein drug product.","authors":"Yuan Cheng, Huu Thuy Trang Duong, Qingyan Hu, Mohammed Shameem, Xiaolin Charlie Tang","doi":"10.1093/abt/tbae030","DOIUrl":"10.1093/abt/tbae030","url":null,"abstract":"<p><p>The development of lyophilized protein drug products is a critical and complex task in the pharmaceutical industry, requiring a comprehensive understanding of the myriad of factors affecting product quality, stability, and the efficiency and robustness of the lyophilization process. This review offers practical advice on the critical aspects of lyophilized protein drug product development. Practical considerations across both the early and late stages of development are discussed, underscoring the necessity of a strategic approach from initial development through to commercialization. The review then delves into formulation optimization strategies that are essential for enhancing protein stability and the efficiency of the lyophilization process. This section outlines stable formulation design and highlights the unique considerations required for high protein concentration lyophilized drug products. It further explores the formulation strategies to enhance the lyophilization process' efficiency. Moreover, the paper examines the critical elements in selecting primary containers and closures for lyophilized drug products, focusing on vials and dual chamber systems. The analysis encompasses the effects of the container/closure's material, size, geometry, and fill volume on product quality and process efficiency. Lastly, the review provides practical considerations in lyophilization cycle development, including the design and optimization of the freezing, primary drying, and secondary drying stages to achieve a robust, scalable, and efficient lyophilization process. By offering comprehensive insights into these key areas to enhance their understanding and implementation of best practices in the field, this paper serves as a useful resource for researchers, formulators, and process engineers involved in the development of lyophilized protein drug products.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"8 1","pages":"13-25"},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 43 hemichannels and related diseases.","authors":"Yanfeng Zhang, Francisca M Acosta, Jean X Jiang","doi":"10.1093/abt/tbae024","DOIUrl":"10.1093/abt/tbae024","url":null,"abstract":"<p><p>Connexin 43 (Cx43) protein forms hemichannels (connexons) and gap junctions, with hemichannels consisting of six Cx43 molecules and gap junctions formed by two hemichannels. While gap junctions are prevalent in organs like the heart and liver, hemichannels are found in specific cell types, such as astrocytes and osteocytes. They allow the passage of small molecules (<1.5 kDa) between the cytoplasm and extracellular matrix. Cx43 hemichannels have emerged as potential therapeutic targets in various diseases, including central nervous system disorders, bone-related diseases, diabetic complications, wound healing, and cancers. Aberrant hemichannel opening can worsen conditions by releasing inflammatory elements, such as causing gliosis in neuronal cells. Conversely, functional hemichannels may inhibit cancer cell growth and metastasis. Recent studies are revealing new mechanisms of Cx43 hemichannels, broadening their therapeutic applications and highlighting the importance of regulating their activity for improved disease outcomes.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"361-369"},"PeriodicalIF":0.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond ADCs: harnessing bispecific antibodies to directly induce apoptosis for targeted tumor eradication.","authors":"Victor S Goldmacher, Iosif M Gershteyn, Yelena Kovtun","doi":"10.1093/abt/tbae029","DOIUrl":"10.1093/abt/tbae029","url":null,"abstract":"<p><p>Bispecific apoptosis triggers (BATs) are innovative bispecific antibodies designed to simultaneously target both a tumor-associated antigen and a cancer cell's death receptor, thereby directly activating the extrinsic apoptotic pathway to induce death of cancer cells. This unique mechanism distinguishes BATs from antibody-drug conjugates (ADCs), which rely on cytotoxic drugs, and bispecific immune cell engagers such as bispecific T-cell engagers (BiTEs) and bispecific natural killer cell engagers (NKCEs), which recruit immune cells to eliminate target cancer cells. BATs offer significant potential advantages in clinical efficacy and safety over ADCs and BiTEs. Although the field is still emerging, recent advancements are highly promising, and analysis of preclinical and clinical data of DR5-targeting antibodies have been pivotal in outlining the criteria for the next generation of effective and safe medicines. Antibodies found inactive in preclinical testing were also found to be clinically ineffective, whereas antibodies with minimal preclinical results demonstrated moderate clinical activity. All clinical DR5-targeting antibodies were well tolerated by patients even at high doses (with the exception of TAS266 due to its unique design). These findings underscore the predictive value of robust preclinical models on clinical outcomes. Notably, first-in-class BAT, Cancerlysin™ IMV-M, demonstrated potent efficacy in diverse xenograft cancer models and safety in non-human primates, marking a significant advancement in developing safe and effective anti-cancer drugs.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"351-360"},"PeriodicalIF":0.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging high-throughput analytics and automation to rapidly develop high-concentration mAb formulations: integrated excipient compatibility and viscosity screening.","authors":"Lun Xin, Lan Lan, Mourad Mellal, Nathan McChesney, Robert Vaughan, Claudia Berdugo, Yunsong Li, Jingtao Zhang","doi":"10.1093/abt/tbae028","DOIUrl":"10.1093/abt/tbae028","url":null,"abstract":"<p><strong>Background: </strong>Formulation screening is essential to experimentally balance stability and viscosity in high-concentration mAb formulations. We developed a high-throughput approach with automated sample preparation and analytical workflows to enable the integrated assessment of excipient compatibility and viscosity of mAb formulations.</p><p><strong>Methods: </strong>Ninety-six formulations of a trastuzumab biosimilar were screened by combining 8 types of excipient modifiers with 4 types of buffers across a pH range of 4.5 to 7.5. Key stability risks, including high molecular weight (HMW) aggregation and fragmentation, were thoroughly assessed along with viscosity at high concentrations. Additionally, several biophysical parameters were evaluated for their ability to predict stability or viscosity outcomes. Multiple linear regression was applied to fit the data and identify key factors.</p><p><strong>Results: </strong>The optimal pH range for the trastuzumab biosimilar was found to be 5.0 to 6.5, based on opposing pH dependencies for stability and viscosity. Buffer type had a minor effect on viscosity and fragmentation but played a significant role in influencing HMW aggregates, with Na-acetate and histidine-HCl being the best candidates. The impact of excipient modifiers on viscosity, HMW, and fragmentation depended on both pH and buffer type, showing strong interactions among factors. Arginine-HCl and lysine-HCl effectively lowered viscosity of the trastuzumab biosimilar at pH levels above 6.0, while glycine formulations were more effective at reducing viscosity below pH 6.0. Histidine-HCl, arginine-HCl, and lysine-HCl lowered the risk of HMW aggregation, whereas formulations containing Na-phosphate or NaCl showed higher HMW aggregation. Formulations with arginine-HCl, lysine-HCl, and NaCl demonstrated a rapid increase in fragmentation at pH levels below 5.0, while Na-aspartate formulations showed increased fragmentation at pH levels above 6.5.</p><p><strong>Conclusion: </strong>Hence, it is important to optimize the levels of each chosen excipient in the formulation study to balance their benefits against potential incompatibilities. This study serves as a foundation for identifying high-concentration antibody formulations using a high-throughput approach, where minimal materials are required, and optimized formulation design spaces can be quickly identified.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"335-350"},"PeriodicalIF":0.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a common light chain bispecific antibody targeting PD-1 and PD-L1 by Hybridoma-to-Phage-to-Yeast (H2PtY) platform.","authors":"Peipei Liu, Chunyin Gu, Xiaodan Cao, Huawei Zhang, Zongda Wang, Yukun Yang, KeDong OuYang, Yingying Zhen, Fangfang Jia, Xianqing He, Haixiang Yu, Sujun Deng","doi":"10.1093/abt/tbae027","DOIUrl":"10.1093/abt/tbae027","url":null,"abstract":"<p><strong>Background: </strong>Therapeutic antibody drugs targeting the PD-1 pathway are generally characterized by relatively low response rates and susceptibility to drug resistance during clinical application. Therefore, there is an urgent need for alternative therapeutic strategies to increase the immune response rate. Bispecific antibodies co-targeting PD-1 and PD-L1 may have greater potential to improve the efficacy of the immune checkpoint pathway.</p><p><strong>Method: </strong>In this study, we developed a potent humanized common light chain (CLC) IgG shape bispecific antibody (bsAb), named JMB2005, based on Hybridoma-to-Phage-to-Yeast platform. The platform allowed us to discover CLC bsAb from traditional mice for any pair of given targets.</p><p><strong>Results: </strong>JMB2005 exhibited favorable developability, good manufacturing property, and satisfactory efficacy, which could be given via subcutaneous injection at the concentration of 120 mg/mL. Mechanistically, JMB2005 could bridge tumor cells and T cells with both Fab arms and promote T-cells to function as direct tumor cell killers. It could also promote T cell activation by blocking the binding of PD-L1 to CD80. Furthermore, JMB2005 has exhibited a favorable half-life and has demonstrated promising anti-tumor therapeutic efficacy <i>in vivo</i>.</p><p><strong>Conclusion: </strong>Consequently, the present study showed that the novel humanized CLC bsAb JMB2005 may represent a novel therapeutic agent of great clinical potential.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"8 1","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-based antibody discovery platform identifies novel, diverse, and pharmacologically active therapeutic antibodies against multiple SARS-CoV-2 strains.","authors":"Cristina Moldovan Loomis, Thomas Lahlali, Danielle Van Citters, Megan Sprague, Gregory Neveu, Laurence Somody, Christine C Siska, Derrick Deming, Andrew J Asakawa, Tileli Amimeur, Jeremy M Shaver, Caroline Carbonelle, Randal R Ketchem, Antoine Alam, Rutilio H Clark","doi":"10.1093/abt/tbae025","DOIUrl":"https://doi.org/10.1093/abt/tbae025","url":null,"abstract":"<p><strong>Background: </strong>We are entering a new era of antibody discovery and optimization where machine learning (ML) processes will become indispensable for the design and development of therapeutics.</p><p><strong>Methods: </strong>We have constructed a Humanoid Antibody Library for the discovery of therapeutics that is an initial step towards leveraging the utility of artificial intelligence and ML. We describe how we began our validation of the library for antibody discovery by isolating antibodies against a target of pandemic concern, SARS-CoV-2. The two main antibody quality aspects that we focused on were functional and biophysical characterization.</p><p><strong>Results: </strong>The applicability of our platform for effective therapeutic antibody discovery is demonstrated here with the identification of a panel of human monoclonal antibodies that are novel, diverse, and pharmacologically active.</p><p><strong>Conclusions: </strong>These first-generation antibodies, without the need for affinity maturation, exhibited neutralization of SARS-CoV-2 viral infectivity across multiple strains and indicated high developability potential.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"307-323"},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Directed protein engineering identifies a human TIM-4 blocking antibody that enhances anti-tumor response to checkpoint inhibition in murine colon carcinoma.","authors":"Karla K Frietze, Kamala Anumukonda, Laura Padula, Natasha Strbo, Neil Goldstein","doi":"10.1093/abt/tbae026","DOIUrl":"10.1093/abt/tbae026","url":null,"abstract":"<p><strong>Background: </strong>T-cell immunoglobulin and mucin domain containing molecule-4 (TIM-4) is a scavenger receptor best known for its role in recognizing dying cells. TIM-4 orchestrates phagocytosis allowing for cellular clearance of apoptotic cells, termed efferocytosis. It was previously shown that TIM-4 directly interacts with AMPKα1, activating the autophagy pathway, leading to degradation of ingested tumors, and effectively reducing antigen presentation.</p><p><strong>Methods: </strong>This study sought to identify a novel human TIM-4 antibody that can prevent phagocytosis of tumor cells thereby allowing for more antigen presentation resulting in anti-tumor immunological response. Using phage display panning directed against human TIM-4, we engineered a novel human TIM-4 antibody (SKWX301). Combination of in vitro phagocytosis assays and cell viability assays were used to test functionality of SKWX301. To examine the effect of SKWX301 in mouse models, we employed a syngeneic mouse model. CT26 cells were subcutaneously injected into BALB/c mice and tumor growth and mouse survival were analyzed.</p><p><strong>Results: </strong>SKWX301 can prevent human macrophage phagocytosis of cancer cells in vitro. Combination of low dose SKWX301 and anti-PD1 antibody significantly inhibited tumor growth and increased overall survival in mice. This demonstrates that SKWX301 is effective in both human in vitro models and mouse in vivo models.</p><p><strong>Conclusion: </strong>Our study has demonstrated a rapid antibody discovery approach and identified a novel human TIM-4 antibody that can serve as a therapeutic for antitumor immunity to improve cancer therapy.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"324-334"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FcRider: a recombinant Fc nanoparticle with endogenous adjuvant activities for hybrid immunization.","authors":"Changchuin Mao, Karen Eberle, Xiaojie Chen, Yiming Zhou, Jun Li, Hong Xin, Wenda Gao","doi":"10.1093/abt/tbae023","DOIUrl":"https://doi.org/10.1093/abt/tbae023","url":null,"abstract":"<p><p>Active immunization (vaccination) induces long-lasting immunity with memory, which takes weeks to months to develop. Passive immunization (transfer of neutralizing antibodies) provides immediate protection, yet with high cost and effects being comparatively short-lived. No currently approved adjuvants are compatible with formulations to combine active and passive immunizations, not to mention their huge disparities in administration routes and dosage. To solve this, we engineered the Fc fragment of human IgG1 into a hexamer nanoparticle and expressed its afucosylated form in Fut8-/- CHO cells, naming it \"FcRider.\" FcRider is highly soluble with long-term stability, easily produced at high levels equivalent to those of therapeutic antibodies, and is amenable to conventional antibody purification schemes. Most importantly, FcRider possesses endogenous adjuvant activities. Using SW_HEL B cell receptor (BCR) transgenic mice, we found that HEL-FcRider induced GL7⁺ germinal center B cells and HEL-specific IgG. Similarly, immunizing mice with UFO-BG-FcRider, a fusion containing the stabilized human immunodeficiency virus-1 (HIV-1) Env protein as immunogen, promoted somatic hypermutation and generation of long CDR3 of the IgG heavy chains. Intramuscular injection of (Fba + Met6)₃-FcRider, a fusion with two peptide epitopes from <i>Candida albicans</i> cell surface, stimulated strong antigen-specific IgG titers. In three different models, we showed that afucosylated FcRider functions as a multivalent immunogen displayer and stimulates antigen-specific B cells without any exogenous adjuvant. As an antibody derivative, afucosylated FcRider could be a novel platform combining vaccines and therapeutic antibodies, integrating active and passive immunizations into single-modality \"hybrid immunization\" to provide complete and long-lasting protection against infections, and may open new avenues in cancer immunotherapy as well.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 4","pages":"295-306"},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pan-allelic human SIRPα-blocking antibody, ES004-B5, promotes tumor killing by enhancing macrophage phagocytosis and subsequently inducing an effective T-cell response.","authors":"Xiaofeng Niu, Chunnian Wang, Haixia Jiang, Rui Gao, Yefeng Lu, Xiaoli Guo, Hongping Zhou, Xue Cui, Jun Sun, Quan Qiu, Dawei Sun, Hongtao Lu","doi":"10.1093/abt/tbae022","DOIUrl":"https://doi.org/10.1093/abt/tbae022","url":null,"abstract":"<p><p>As a major immune cell type in the tumor microenvironment, tumor-associated macrophages secrete suppressive factors that can inhibit antitumor immunity and promote tumor progression. One approach trying to utilize macrophages for immunotherapy has been to block the CD47-SIRPα axis, which mediates inhibitory signaling, to promote phagocytosis of tumor cells. Many CD47-targeted agents, namely, anti-CD47 antibodies and SIRPα fusion proteins, were associated with a diverse spectrum of toxicities that limit their use in clinical settings. Universal expression of CD47 also leads to a severe \"antigen sink\" effect of CD47-targeted agents. Given that the CD47 receptor, SIRPα, has a more restricted expression profile and may have CD47-independent functions, targeting SIRPα is considered to have distinct advantages in improving clinical efficacy with a better safety profile. We have developed ES004-B5, a potentially best-in-class pan-allelic human SIRPα-blocking antibody using hybridoma technology. ES004-B5 binds to major human SIRPα variants through a unique epitope with high affinity. By blocking CD47-induced inhibitory \"don't-eat-me\" signaling, ES004-B5 exerts superior antitumor activity in combination with anti-tumor-associated antigen antibodies <i>in vitro</i> and <i>in vivo</i>. Unlike CD47-targeted agents, ES004-B5 exhibits an excellent safety profile in nonhuman primates. ES004-B5 has potential to be an important backbone for SIRPα-based combination therapy and/or bispecific antibodies, which will likely overcome the limitations of CD47-targeted agents encountered in clinical settings.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"266-280"},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11384143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}