Antibody Therapeutics最新文献

{"title":"Multiple approaches to reduce reconstitution time of lyophilized drug products with high protein concentration","authors":"Xiaozhang Zhang, Ningning Zhou, Chunsheng Yang, Zhaowei Jin, Jeremy Guo","doi":"10.1093/abt/tbad031","DOIUrl":"https://doi.org/10.1093/abt/tbad031","url":null,"abstract":"Lyophilized drug products with high protein concentration often perform long reconstitution time, which is inconvenient for clinical use. The objective of this work is to achieve short reconstitution time with multiple and combined strategies. In this paper, we describe the following approaches that lead to reduction of reconstitution time. In terms of lyophilization process, using annealing step during freezing can increase the pore size of lyophilized cake, and decreasing headspace pressure in vial before stoppering can also help solvent penetrate through lyophilized cake. Regarding to formulations, it is an effective strategy of decreasing protein concentration or reducing diluent volume to achieve high protein concentration after reconstitution. Considering container size, high surface-area-to-height ratio of the cakes is also beneficial for reduction of reconstitution time. In addition, reconstitution methods, for example, increasing frequency of swirling and diluent temperature are also helpful to reduce reconstitution time. Among these strategies, reducing diluent volume to achieve high protein concentration and reducing headspace pressure show markedly reduction of reconstitution time. Moreover, we propose combined strategies to mitigate the reconstitution time, at the same time, to achieve same target dose in clinics. The combination of all factors can achieve the overall reduction ratio of 98%, and will not influence the product quality. Therefore, this paper provides insights on the application of multiple strategies to accelerate the reconstitution of lyophilized drug products with high concentration, and facilitates their widespread clinical application.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"70 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139146021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACE2-Fc and DPP4-Fc decoy receptors against SARS-CoV-2 and MERS-CoV variants: A quick therapeutic option for current and future coronaviruses outbreaks","authors":"M. Alfaleh, R. Alsulaiman, S. Almahboub, Leena Nezamuldeen, A. Zawawi, Najwa D. Aljehani, Muhammad Yasir, Rwaa H Abdulaal, Rami Alkhaldi, Assala Helal, S. S. Alamri, Jana S. Malki, R. Alhabbab, T. Abujamel, Nabil A Alhakamy, Aisha Alnami, A. Algaissi, Mazen Hassanain, A. Hashem","doi":"10.1093/abt/tbad030","DOIUrl":"https://doi.org/10.1093/abt/tbad030","url":null,"abstract":"\u0000 \u0000 \u0000 The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the Middle East respiratory syndrome coronavirus (MERS-CoV) are highly pathogenic human coronaviruses (CoVs). Anti-CoVs mAbs and vaccines may be effective, but the emergence of neutralization escape variants is inevitable.\u0000 \u0000 \u0000 \u0000 Angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 enzyme (DPP4) are the getaway receptors for SARS-CoV-2 and MERS-CoV, respectively. Thus, we reformatted these receptors and expressed them as recombinant Fc-fusion decoy receptors. Then we tested them in parallel with anti-SARS-CoV (ab1-IgG) and anti-MERS-CoV (M336-IgG) mAbs in ELISA and against several pseudotyped SARS-CoV-2 and MERS-CoV variants using pseudovirus neutralization assay.\u0000 \u0000 \u0000 \u0000 The generated Fc-based decoy receptors exhibited a strong inhibitory effect against all pseudotyped CoVs. Results showed that although mAbs can be effective antiviral drugs, they might rapidly lose their efficacy against highly mutated viruses, as shown with ab1-IgG against some of the SARS-CoV-2 variants.\u0000 \u0000 \u0000 \u0000 We suggest that receptor traps can be engineered as Fc-fusion proteins for highly mutating viruses with known entry receptors, for a faster and effective therapeutic response even against virus harboring antibodies escape mutations.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"19 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138977196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next generation of multispecific antibody engineering","authors":"Daniel Keri, Matt Walker, Isha Singh, Kyle Nishikawa, Fernando Garces","doi":"10.1093/abt/tbad027","DOIUrl":"https://doi.org/10.1093/abt/tbad027","url":null,"abstract":"\u0000 Multispecific antibodies recognize two or more epitopes located on the same or distinct targets. This added capability through protein design allows these man-made molecules to address unmet medical needs that are no longer possible with single targeting such as with monoclonal antibodies or cytokines alone. However, the approach to the development of these multispecific molecules has been met with numerous road bumps, which suggests that a new workflow for multispecific molecules is required. The investigation of the molecular basis that mediates the successful assembly of the building blocks into non-native quaternary structures will lead to the writing of a playbook for multispecifics. This is a must do if we are to design workflows that we can control and in turn predict success. Here, we reflect on the current state-of-the-art of therapeutic biologics and look at the building blocks, in terms of proteins, and tools that can be used to build the foundations of such a next-generation workflow.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"48 35","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138588638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD80-fc fusion protein as a potential cancer immunotherapy strategy","authors":"Songna Wang, Pinliang Hu, Jiajun Fan, Jing Zou, Weidong Hong, Xuan Huang, Dan-Ling Pan, Huaning Chen, Yi Zhun Zhu, Liping Ye","doi":"10.1093/abt/tbad029","DOIUrl":"https://doi.org/10.1093/abt/tbad029","url":null,"abstract":"The activation of T lymphocytes is a crucial component of the immune response, and the presence of CD80, a membrane antigen, is necessary for T-cell activation. CD80 is usually expressed on antigen-presenting cells (APCs), which can interact with cluster of differentiation 28 (CD28) or programmed cell death ligand 1 (PD-L1) to promote T-cell proliferation, differentiation and function by activating costimulatory signal or blocking inhibitory signal. Simultaneously, CD80 on the APCs also interacts with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells to suppress the response of specific effector T cells, particularly in the context of persistent antigenic stimulation. Due to the pivotal role of CD80 in the immune response, the CD80-Fc fusion protein has emerged as a promising approach for cancer immunotherapy. This review primarily focused on the crucial role of CD80 in the cancer immunotherapy. We also reviewed the current advancements in the research of CD80-Fc fusion proteins. Finally, we deliberated on the challenges encountered by CD80-Fc fusion proteins and proposed the potential strategies that could yield the benefits for patients.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"287 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139205249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges and solutions for the downstream purification of therapeutic proteins","authors":"Shuo Tang, Jiaoli Tao, Ying Li","doi":"10.1093/abt/tbad028","DOIUrl":"https://doi.org/10.1093/abt/tbad028","url":null,"abstract":"The innovation in recombinant protein technology has brought forth a host of challenges related to the purification of these therapeutic proteins. This article delves into the intricate landscape of developing purification processes for artificially designed therapeutic proteins. The key hurdles include controlling protein reduction, protein capture, ensuring stability, eliminating aggregates, removing host cell proteins (HCPs), and optimizing protein recovery. In this review, we outline the purification strategies in order to obtain products of high purity, highlighting the corresponding solutions to circumvent the unique challenges presented by recombinant therapeutic proteins, and exemplify the practical applications by case studies. Finally, a perspective towards future purification process development is provided.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139259902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the protein-protein interactome in the tumor immune microenvironment","authors":"Rui Peng, Mi Deng","doi":"10.1093/abt/tbad026","DOIUrl":"https://doi.org/10.1093/abt/tbad026","url":null,"abstract":"Abstract The cell-to-cell communication primarily occurs through cell-surface and secreted proteins, which form a sophisticated network that coordinates systemic immune function. Uncovering these protein-protein interactions (PPIs) is indispensable for understanding the molecular mechanism and elucidating immune system aberrances under diseases. Traditional biological studies typically focus on a limited number of PPI pairs due to the relative low throughput of commonly used techniques. Encouragingly, classical methods have advanced, and many new systems tailored for large-scale protein-protein screening have been developed and successfully utilized. These high-throughput PPI investigation techniques have already made considerable achievements in mapping the immune cell interactome, enriching PPI databases and analysis tools, and discovering therapeutic targets for cancer and other diseases, which will definitely bring unprecedented insight into this field.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"113 12","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134957190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fc gamma receptors promote antibody induced LILRB4 internalization and immune regulation of monocytic AML","authors":"Joshua W Morse, Xun Gui, Mi Deng, Ryan Huang, Xiaohua Ye, Peng Zhao, Xuejun Fan, Wei Xiong, Cheng Cheng Zhang, Ningyan Zhang, Zhiqiang An","doi":"10.1093/abt/tbad025","DOIUrl":"https://doi.org/10.1093/abt/tbad025","url":null,"abstract":"Abstract Background The immune checkpoint leukocyte immunoglobulin-like receptor B4 (LILRB4) is found specifically on the cell surface of acute monocytic leukemia (monocytic AML), an aggressive and common subtype of AML. We have developed a humanized monoclonal IgG1 LILRB4-blocking antibody (h128–3), which improved immune regulation but reduced cell surface expression of LILRB4 in monocytic AML models by 40–60%. Interestingly, most of this effect was neutralized by mutation of the Fc region of the antibody (h128–3/N297A) which prevents interaction with Fc gamma receptors (FcγRs). This suggested that there is FcγR-dependent antigenic modulation underlying h128–3’s effects, a mechanism known to alter the function of antibodies targeting B-cell malignancies. Methods We disrupted the Fc-FcγR interaction pharmacologically and with stable CRISPR-Cas9-mediated genetic knockout of FcγRs in monocytic AML cell lines to investigate the role of FcγR-dependent antigenic modulation in the regulation of LILRB4 by h128–3. Results When FcγRI is inhibited or removed from the surface of monocytic AML cells, h128–3 cannot optimally perform its blocking function, resulting in activation of the LILRB4 inhibitory receptor and leading to a 15–25% decrease in T cell-mediated cytotoxicity in vitro. In the absence of FcγRI, scaffolding by FcγRIIa allows h128–3 to maintain LILRB4-blocking function. Conclusions Here we define a FcγR-dependent antigenic modulation mechanism underlying the function of an immunoreceptor blocking antibody for the first time in myeloid malignancy. This research will facilitate the development of safe, precision-targeted antibody therapeutics in myeloid malignancies with greater potency and efficacy.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"4 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135975635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A disruptive clickable antibody design for the generation of antibody-drug conjugates","authors":"Nathanaël Rakotoarinoro, Yan F K Dyck, Simon K Krebs, Miriam-Kousso Assi, Maria K Parr, Marlitt Stech","doi":"10.1093/abt/tbad023","DOIUrl":"https://doi.org/10.1093/abt/tbad023","url":null,"abstract":"Abstract Background: Antibody-drug conjugates are cancer therapeutics that combine specificity and toxicity. A highly cytotoxic drug is covalently attached to an antibody that directs it to cancer cells. The conjugation of the drug-linker to the antibody is a key point in research and development as well as in industrial production. The consensus is to conjugate the drug to a surface-exposed part of the antibody to ensure maximum conjugation efficiency. However, the hydrophobic nature of the majority of drugs used in antibody-drug conjugates leads to an increased hydrophobicity of the generated antibody-drug conjugates, resulting in higher liver clearance and decreased stability. Methods: In contrast, we describe a non-conventional approach in which the drug is conjugated in a buried part of the antibody. To achieve this, a ready-to-click antibody design was created in which an azido-based non-canonical amino acid is introduced within the Fab cavity during antibody synthesis using nonsense suppression technology. The Fab cavity was preferred over the Fc cavity to circumvent issues related to cleavage of the IgG1 lower hinge region in the tumor microenvironment. Results: This antibody design significantly increased the hydrophilicity of the generated antibody-drug conjugates compared to the current best-in-class designs based on non-canonical amino acids, while conjugation efficiency and functionality were maintained. The robustness of this native shielding effect and the versatility of this approach were also investigated. Conclusions: This pioneer design may become a starting point for the improvement of antibody-drug conjugates and an option to consider for protecting drugs and linkers from unspecific interactions. Statement of significance: This work describes for the first time to our knowledge a ready-to-click antibody design based on non-canonical amino acids enabling the generation of highly hydrophilic antibody-drug conjugates and highlights the importance of the conjugation site selection as well as the drug-linker design for the generation of less hydrophobic antibody-drug conjugates.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"15 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136377266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vitro</i> generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2","authors":"Dora Buzas, H Adrian Bunzel, Oskar Staufer, Emily J Milodowski, Grace L Edmunds, Joshua C Bufton, Beatriz V Vidana Mateo, Sathish K N Yadav, Kapil Gupta, Charlotte Fletcher, Maia Kavanagh Williamson, Alexandra Harrison, Ufuk Borucu, Julien Capin, Ore Francis, Georgia Balchin, Sophie Hall, Mirella Vivoli Vega, Fabien Durbesson, Srikanth Lingappa, Renaud Vincentelli, Joe Roe, Linda Wooldridge, Rachel Burt, J L Ross Anderson, Adrian J Mulholland, Jonathan Hare, Mick Bailey, Andrew D Davidson, Adam Finn, David Morgan, Jamie Mann, Joachim Spatz, Frederic Garzoni, Christiane Schaffitzel, Imre Berger","doi":"10.1093/abt/tbad024","DOIUrl":"https://doi.org/10.1093/abt/tbad024","url":null,"abstract":"Abstract Background Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens. Methods Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron. Conclusion Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"80 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135993808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Arginine in therapeutic protein formulations: a decade review and perspectives","authors":"Steven Ren","doi":"10.1093/abt/tbad022","DOIUrl":"https://doi.org/10.1093/abt/tbad022","url":null,"abstract":"Abstract Arginine (Arg) is a natural amino acid with an acceptable safety profile and a unique chemical structure. Arg and its salts are highly effective in enhancing protein refolding and solubilization, suppressing protein–protein interaction and aggregation and reducing viscosity of high concentration protein formulations. Arg and its salts have been used in research and 20 approved protein injectables. This review summarizes the effects of Arg as an excipient in therapeutic protein formulations with the focus on its physicochemical properties, safety, applications in approved protein products, beneficial and detrimental effects in liquid and lyophilized protein formulations when combined with different counterions and mechanism on protein stabilization and destabilization. The decade literature review indicates that the benefits of Arg overweigh its risks when it is used appropriately. It is recommended to add Arg along with glutamate as a counterion to high concentration protein formulations on top of sugars or polyols to counterbalance the negative effects of Arg hydrochloride. The use of Arg as a viscosity reducer and protein stabilizer in high concentration formulations will be the inevitable future trend of the biopharmaceutical industry for subcutaneous administration.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"58 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136015715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}