IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-08-27 DOI: 10.1080/19420862.2024.2394230

Fortunato Ferrara, Adeline Fanni, Andre A R Teixeira, Esteban Molina, Camila Leal-Lopes, Ashley DeAguero, Sara D'Angelo, M Frank Erasmus, Laura Spector, Luis Antonio Rodriguez Carnero, Jianquan Li, Thomas J Pohl, Nikolai Suslov, Klervi Desrumeaux, Conor McMahon, Sagar Kathuria, Andrew R M Bradbury

{"title":"A next-generation Fab library platform directly yielding drug-like antibodies with high affinity, diversity, and developability.","authors":"Fortunato Ferrara, Adeline Fanni, Andre A R Teixeira, Esteban Molina, Camila Leal-Lopes, Ashley DeAguero, Sara D'Angelo, M Frank Erasmus, Laura Spector, Luis Antonio Rodriguez Carnero, Jianquan Li, Thomas J Pohl, Nikolai Suslov, Klervi Desrumeaux, Conor McMahon, Sagar Kathuria, Andrew R M Bradbury","doi":"10.1080/19420862.2024.2394230","DOIUrl":"10.1080/19420862.2024.2394230","url":null,"abstract":"We previously described an in vitro single-chain fragment (scFv) library platform originally designed to generate antibodies with excellent developability properties. The platform design was based on the use of clinical antibodies as scaffolds into which replicated natural complementarity-determining regions purged of sequence liabilities were inserted, and the use of phage and yeast display to carry out antibody selection. In addition to being developable, antibodies generated using our platform were extremely diverse, with most campaigns yielding sub-nanomolar binders. Here, we describe a platform advancement that incorporates Fab phage display followed by single-chain antibody-binding fragment Fab (scFab) yeast display. The scFab single-gene format provides balanced expression of light and heavy chains, with enhanced conversion to IgG, thereby combining the advantages of scFvs and Fabs. A meticulously engineered, quality-controlled Fab phage library was created using design principles similar to those used to create the scFv library. A diverse panel of binding scFabs, with high conversion efficiency to IgG, was isolated against two targets. This study highlights the compatibility of phage and yeast display with a Fab semi-synthetic library design, offering an efficient approach to generate drug-like antibodies directly, facilitating their conversion to potential therapeutic candidates.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2394230"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Coactivation of Tie2 and Wnt signaling using an antibody-R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia. 使用抗体-R-软骨素融合体共同激活 Tie2 和 Wnt 信号，可增强后肢缺血时的治疗性血管生成和血管稳定。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-11-28 DOI: 10.1080/19420862.2024.2435478

Byungtae Hwang, Min-Young Jeon, Ju-Hong Jang, Young-Lai Cho, Dong Gwang Lee, Jeong-Ki Min, Jangwook Lee, Jong-Gil Park, Ji-Hun Noh, Wonjun Yang, Nam-Kyung Lee

{"title":"Coactivation of Tie2 and Wnt signaling using an antibody-R-spondin fusion potentiates therapeutic angiogenesis and vessel stabilization in hindlimb ischemia.","authors":"Byungtae Hwang, Min-Young Jeon, Ju-Hong Jang, Young-Lai Cho, Dong Gwang Lee, Jeong-Ki Min, Jangwook Lee, Jong-Gil Park, Ji-Hun Noh, Wonjun Yang, Nam-Kyung Lee","doi":"10.1080/19420862.2024.2435478","DOIUrl":"10.1080/19420862.2024.2435478","url":null,"abstract":"Therapeutic angiogenesis by intentional formation of blood vessels is essential for treating various ischemic diseases, including limb ischemia. Because Wnt/β-catenin and angiopoietin-1/Tie2 signaling play important roles in endothelial survival and vascular stability, coactivation of these signaling pathways can potentially achieve therapeutic angiogenesis. In this study, we developed a bifunctional antibody fusion, consisting of a Tie2-agonistic antibody and the Furin domains of R-spondin 3 (RSPO3), to simultaneously activate Tie2 and Wnt/β-catenin signaling. We identified a Tie2-agonistic antibody T11 that cross-reacted with the extracellular domain of human and mouse Tie2, and evaluated its ability to increase endothelial cell survival and tube formation. We generated a bifunctional T11-RF12 by fusing T11 with the Furin-1 and -2 domains of RSPO3. T11-RF12 could bind not only to Tie2, but also to LGR5 and ZNRF3, which are counterparts of the Furin-1 and -2 domains. T11-RF12 significantly increased Wnt/β-catenin signaling, as well as the formation of capillary-like endothelial tubes, regardless of the presence of Wnt ligands. Coactivation of Tie2 and Wnt/β-catenin signaling by T11-RF12 increased the blood flow, and thereby reduced foot necrosis in a mouse hindlimb ischemia model. In particular, T11-RF12 induced therapeutic angiogenesis by promoting vessel stabilization through pericyte coverage and retaining endothelial expression of Frizzled 10 and active β-catenin. These results indicate that the agonistic synergism of Tie2 and Wnt/β-catenin signaling achieved using T11-RF12 is a novel therapeutic option with potential for treating limb ischemia and other ischemic diseases.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2435478"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Agonistic anti-NKG2D antibody structure reveals unique stoichiometry and epitope compared to natural ligands. 与天然配体相比，激动型抗 NKG2D 抗体结构揭示了独特的化学计量学和表位。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-11-25 DOI: 10.1080/19420862.2024.2433121

Daniel Fallon, Ching-Shin Huang, Jingya Ma, Christopher Morgan, Zhaohui Sunny Zhou

引用次数: 0

Correction. 更正。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-05-12 DOI: 10.1080/19420862.2024.2354626

引用次数: 0

Structural analysis of light chain-driven bispecific antibodies targeting CD47 and PD-L1. 针对 CD47 和 PD-L1 的轻链驱动双特异性抗体的结构分析。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-06-07 DOI: 10.1080/19420862.2024.2362432

Pauline Malinge, Xavier Chauchet, Jérémie Bourguignon, Nicolas Bosson, Sébastien Calloud, Tereza Bautzova, Marie Borlet, Mette Laursen, Vinardas Kelpsas, Nadia Rose, Franck Gueneau, Ulla Ravn, Giovanni Magistrelli, Nicolas Fischer

{"title":"Structural analysis of light chain-driven bispecific antibodies targeting CD47 and PD-L1.","authors":"Pauline Malinge, Xavier Chauchet, Jérémie Bourguignon, Nicolas Bosson, Sébastien Calloud, Tereza Bautzova, Marie Borlet, Mette Laursen, Vinardas Kelpsas, Nadia Rose, Franck Gueneau, Ulla Ravn, Giovanni Magistrelli, Nicolas Fischer","doi":"10.1080/19420862.2024.2362432","DOIUrl":"10.1080/19420862.2024.2362432","url":null,"abstract":"In contrast to natural antibodies that rely mainly on the heavy chain to establish contacts with their cognate antigen, we have developed a bispecific antibody format in which the light chain (LC) drives antigen binding and specificity. To better understand epitope-paratope interactions in this context, we determined the X-ray crystallographic structures of an antigen binding fragment (Fab) in complex with human CD47 and another Fab in complex with human PD-L1. These Fabs contain a κ-LC and a λ-LC, respectively, which are paired with an identical heavy chain (HC). The structural analysis of these complexes revealed the dominant contribution of the LCs to antigen binding, but also that the common HC provides some contacts in both CD47 and PD-L1 Fab complexes. The anti-CD47 Fab was affinity optimized by diversifying complementary-determining regions of the LC followed by phage display selections. Using homology modeling, the contributions of the amino acid modification to the affinity increase were analyzed. Our results demonstrate that, despite a less prominent role in natural antibodies, the LC can mediate high affinity binding to different antigens and neutralize their biological function. Importantly, Fabs containing a common variable heavy (VH) domain enable the generation of bispecific antibodies retaining a truly native structure, maximizing their therapeutic potential.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2362432"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of the high concentration viscosity of IgG₁ antibodies using clinically validated Fc mutations. 利用临床验证的 Fc 突变调节 IgG1 抗体的高浓度粘度。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-19 DOI: 10.1080/19420862.2024.2379560

Joel Heisler, Daniel Kovner, Saeed Izadi, Jonathan Zarzar, Paul J Carter

{"title":"Modulation of the high concentration viscosity of IgG1 antibodies using clinically validated Fc mutations.","authors":"Joel Heisler, Daniel Kovner, Saeed Izadi, Jonathan Zarzar, Paul J Carter","doi":"10.1080/19420862.2024.2379560","DOIUrl":"10.1080/19420862.2024.2379560","url":null,"abstract":"The self-association of therapeutic antibodies can result in elevated viscosity and create problems in manufacturing and formulation, as well as limit delivery by subcutaneous injection. The high concentration viscosity of some antibodies has been reduced by variable domain mutations or by the addition of formulation excipients. In contrast, the impact of Fc mutations on antibody viscosity has been minimally explored. Here, we studied the effect of a panel of common and clinically validated Fc mutations on the viscosity of two closely related humanized IgG1, κ antibodies, omalizumab (anti-IgE) and trastuzumab (anti-HER2). Data presented here suggest that both Fab-Fab and Fab-Fc interactions contribute to the high viscosity of omalizumab, in a four-contact model of self-association. Most strikingly, the high viscosity of omalizumab (176 cP) was reduced 10.7- and 2.2-fold by Fc modifications for half-life extension (M252Y:S254T:T256E) and aglycosylation (N297G), respectively. Related single mutations (S254T and T256E) each reduced the viscosity of omalizumab by ~6-fold. An alternative half-life extension Fc mutant (M428L:N434S) had the opposite effect in increasing the viscosity of omalizumab by 1.5-fold. The low viscosity of trastuzumab (8.6 cP) was unchanged or increased by <math><mo>≤</mo></math>2-fold by the different Fc variants. Molecular dynamics simulations provided mechanistic insight into the impact of Fc mutations in modulating electrostatic and hydrophobic surface properties as well as conformational stability of the Fc. This study demonstrates that high viscosity of some IgG1 antibodies can be mitigated by Fc mutations, and thereby offers an additional tool to help design future antibody therapeutics potentially suitable for subcutaneous delivery.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2379560"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy. 发现并开发用于癌症免疫疗法的 IL-2/anti-IL-2 抗体融合蛋白 ANV419，它具有强大的 CD8+ T 细胞和自然杀伤细胞刺激能力。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-23 DOI: 10.1080/19420862.2024.2381891

Patrizia Murer, Barbara Brannetti, Jean-Michel Rondeau, Laetitia Petersen, Nicole Egli, Simone Popp, Catherine Regnier, Kirsten Richter, Andreas Katopodis, Christoph Huber

{"title":"Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy.","authors":"Patrizia Murer, Barbara Brannetti, Jean-Michel Rondeau, Laetitia Petersen, Nicole Egli, Simone Popp, Catherine Regnier, Kirsten Richter, Andreas Katopodis, Christoph Huber","doi":"10.1080/19420862.2024.2381891","DOIUrl":"10.1080/19420862.2024.2381891","url":null,"abstract":"Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8+ T cells and natural killer (NK) cells over Tregs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2+ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2381891"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11268257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction. 更正。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-28 DOI: 10.1080/19420862.2024.2335597

引用次数: 0

Systematic analysis of Fc mutations designed to enhance binding to Fc-gamma receptors. 系统分析旨在增强与 Fc-gamma 受体结合的 Fc 突变。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-09-22 DOI: 10.1080/19420862.2024.2406539

Geoff Hale, Alastair Douglas Davy, Ian Wilkinson

引用次数: 0

Molecular surface descriptors to predict antibody developability: sensitivity to parameters, structure models, and conformational sampling. 预测抗体可开发性的分子表面描述符：对参数、结构模型和构象取样的敏感性。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-06-10 DOI: 10.1080/19420862.2024.2362788

Eliott Park, Saeed Izadi

{"title":"Molecular surface descriptors to predict antibody developability: sensitivity to parameters, structure models, and conformational sampling.","authors":"Eliott Park, Saeed Izadi","doi":"10.1080/19420862.2024.2362788","DOIUrl":"10.1080/19420862.2024.2362788","url":null,"abstract":"In silico assessment of antibody developability during early lead candidate selection and optimization is of paramount importance, offering a rapid and material-free screening approach. However, the predictive power and reproducibility of such methods depend heavily on the selection of molecular descriptors, model parameters, accuracy of predicted structure models, and conformational sampling techniques. Here, we present a set of molecular surface descriptors specifically designed for predicting antibody developability. We assess the performance of these descriptors by benchmarking their correlations with an extensive array of experimentally determined biophysical properties, including viscosity, aggregation, hydrophobic interaction chromatography, human pharmacokinetic clearance, heparin retention time, and polyspecificity. Further, we investigate the sensitivity of these surface descriptors to methodological nuances, such as the choice of interior dielectric constant, hydrophobicity scales, structure prediction methods, and the impact of conformational sampling. Notably, we observe systematic shifts in the distribution of surface descriptors depending on the structure prediction method used, driving weak correlations of surface descriptors across structure models. Averaging the descriptor values over conformational distributions from molecular dynamics mitigates the systematic shifts and improves the consistency across different structure prediction methods, albeit with inconsistent improvements in correlations with biophysical data. Based on our benchmarking analysis, we propose six in silico developability risk flags and assess their effectiveness in predicting potential developability issues for a set of case study molecules.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2362788"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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