mAbs最新文献

{"title":"<i>Alpseq</i>: an open-source workflow to turbocharge nanobody discovery with high-throughput sequencing.","authors":"Kathleen Zeglinski, Jakob Schuster, Jaison D Sa, Amy Adair, Jing Deng, Phillip Pymm, Matthew E Ritchie, Rory Bowden, Wai-Hong Tham, Quentin Gouil","doi":"10.1080/19420862.2026.2623326","DOIUrl":"10.1080/19420862.2026.2623326","url":null,"abstract":"<p><p>Nanobodies have emerged as promising tools for many biotechnological applications due to their small size, high stability and remarkable binding specificity. Next-Generation Sequencing (NGS) enables deep profiling of large nanobody libraries and panning campaigns; however, the scale and diversity of nanobody NGS datasets presents a significant bioinformatic challenge. To this end, we have developed <i>alpseq</i>, an optimized, open-source software pipeline designed specifically for the efficient and accurate processing of NGS data from nanobody libraries and panning campaigns. <i>alpseq</i> is also paired with a PCR-free sequencing library preparation protocol to allow researchers to easily generate their own data while avoiding biases. The <i>alpseq</i> software pipeline is composed of two parts: a pre-processing module written in Nextflow efficiently handles raw nanobody reads in a single line of code. These results are then fed into the analysis module, which contains a comprehensive suite of functions for quality control, diversity analysis, identification of enriched sequences and clustering. <i>alpseq</i> also creates a user-friendly interactive report which empowers scientists to explore their data without the need for extensive bioinformatic experience. Sophisticated panning campaign designs are supported, such as replicates and comparisons between different pans to find cross-binding leads. <i>alpseq</i> thus generates insights into the nanobody selection process and delivers a list of lead candidates for further experimental validation and downstream applications. <i>alspeq</i> is available at https://github.com/kzeglinski/alpseq.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2623326"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12885427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106112","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}

{"title":"A NANOBODY molecule that blocks MerTK ectodomain cleavage in vitro and in vivo.","authors":"Linde Duprez, Ayse Kilic, Hélène Bruwiere, Karim Fekir, Dennis Vlaeminck, Camille De Craene, Daan Geiregat, Kirsten Paesen, Lien Leutenez, Stijn Lambrecht, Thomas Van De Velde, Aline Moliere, Judith Verhelst, Edith Stuyven, Soraya Hoelper, Dieter Schmoll","doi":"10.1080/19420862.2026.2704449","DOIUrl":"10.1080/19420862.2026.2704449","url":null,"abstract":"<p><p>The membrane receptor MerTK is critical for the resolution of inflammation and thus is of pharmacological interest. MerTK function is inhibited by the proteolytic cleavage of its extracellular domain leading to the formation of soluble Mer (sMer). We describe here the NANOBODY molecule A0445046C08 and its half-life-extended version A044500050. Both bound selectively to MerTK and blocked lipopolysaccharide-induced MerTK cleavage in primary macrophages without influencing ligand binding or kinase activity of MerTK. A044500050 reduced Zymosan-induced sMer levels in the peritoneal lavage fluid of a mouse model with sterile peritonitis. The study demonstrates that NANOBODY molecules can be generated that selectively inhibit ectodomain shedding and outlines a novel pharmacological approach for targeting membrane proteins where aberrant cleavage plays a pathogenic role.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2704449"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13378718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456235","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}

{"title":"Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors.","authors":"Welbeck Danquah, Mélanie Pichery, Thomas Eden, Aurelien Boyance, Lise Pasquet, Virginie Roure, Marion Mars, Alice Marchand, Ellen Gumz, Mylène Gador, Lou Valente, Marion Contini, Lukas Czernecki, Sanjith Shanmuganathan, Pauline Barron, Sophie Chabot, Markus Dangl, Gerhard Niederfellner","doi":"10.1080/19420862.2026.2684378","DOIUrl":"10.1080/19420862.2026.2684378","url":null,"abstract":"<p><p>CD3 T cell engagers (TCEs) have transformed hematologic oncology, but dose-liming toxicity and the absence of adequate costimulation have limited TCE success in solid tumors. Consequently, to date, only one classical TCE developed for solid tumors - tarlatamab - has been granted a marketing approval. Here, we report a pioneer combination strategy using a novel CD2-targeted costimulatory bispecific antibody to overcome these limitations. Building on a unique non-blocking CD2 antibody, we developed a HER2×CD2 proof-of-concept bispecific that, combined with an EpCAM×CD3 TCE, provides tumor-dependent costimulation and enhances anti-tumor cytotoxicity mediated by the TCE. We show that HER2×CD2 can be dosed independently to restore optimal anti-tumor cytotoxicity of a sub-efficacious low dose of the EpCAM×CD3 TCE, thus providing a route to avoid TCE-driven toxicity while maintaining efficacy. In a humanized xenograft model, co-treatment with HER2×CD2 achieved complete tumor remission in 8 of 9 mice at a TCE dose that otherwise mediated complete remission in only 1 of 9 mice. We show that HER2×CD2 compensates for the loss of CD58 expression by tumor cells - a well-documented tumor escape mechanism. Notably, unlike CD28-based costimulation, HER2×CD2 effectively also harnessed the anti-tumor cytotoxicity of CD28-negative CD8 T cells - a potent cytotoxic subset prevalent in elderly patients and dominant in solid tumors. Furthermore, HER2×CD2 induced markedly lower cytokine release than a HER2×CD28 bispecific while mediating comparable improvement in anti-tumor cytotoxicity. These findings establish our novel CD2-targeted costimulatory bispecific antibody approach as a promising and potentially safe way to expand and enhance TCE immunotherapy for solid tumors.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2684378"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148218403","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}

{"title":"Glycosylation penetrance of N-X-S/T sequons in antibody variable domains: a structural survey of 19,265 human antibody structures reassessing the histidine/glutamine suppression hypothesis.","authors":"Christopher L Gaughan","doi":"10.1080/19420862.2026.2703349","DOIUrl":"10.1080/19420862.2026.2703349","url":null,"abstract":"<p><p>Machine learning (ML) approaches for de novo antibody design generate thousands of candidate sequences, but most lack a robust assessment of post-translational modification liabilities. N-linked glycosylation in variable domains can fundamentally alter antibody function, yet current penetrance estimates are derived from glycosylation-enriched datasets inflating risk estimates. We surveyed 19,265 human antibody structures from the Protein Data Bank (PDB), identifying 1,368 N-X-S/T sequons in variable domains (this study) with 7.82% observed penetrance (107/1,368; Wilson 95% CI 6.5-9.4%) - a crystallographic lower bound reflecting selection against glycosylated structures in the PDB - compared with 16.47% from a previously published glycosylation-enriched corpus. At the X-position, no glycosylation was observed at histidine (0/61; Wilson 95% upper bound 5.9%), lysine (0/26; upper bound 12.9%), or tryptophan (0/26), consistent with suppression. Glutamine showed 6.45% penetrance (2/31), indistinguishable from baseline and refuting its prior classification as a suppressor. Variable light domains showed higher aggregate penetrance than variable heavy (9.62% vs 6.79%; Fisher OR = 1.46, <i>p</i> = 0.075), though this contrast did not survive joint Bayesian adjustment. Regionally, FR2 was glycosylation-resistant (0/119) while FR1 (14.0%) and FR4 (12.1%) showed elevated rates. N-X-T sequons were 3.84-fold more susceptible than N-X-S in aggregate (13.64% vs 3.55%; Fisher exact <i>p</i> = 8.13 × 10^-12, OR = 4.29). An independent PDB-overlap-free validation subset (<i>n</i> = 449, 33 glycosylation events, 189 nonoverlapping PDBs) reproduced the central findings. Leakage-corrected Bayesian logistic regression confirmed the N-X-T preference as the most prior-stable effect and identified strong negative coefficients for proline and aromatic residues at the +3 position immediately C-terminal to the sequon; the histidine effect at the X-position was borderline under prior sensitivity. We present a confidence-interval-aware decision tree that integrates X-position, third-position, chain type, and regional context as a sequence-only triage instrument for ML-designed antibody candidates.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2703349"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549472","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}

{"title":"NMR detects clustering and ultra-weak excipient interactions governing monoclonal antibody viscosity in formulation-relevant conditions.","authors":"Liza Boëffard-Dosierre, Camille Dagallier, Géraldine Eudier, Vasco Filipe, Atifa Badar-Majeed, Solène Fraumont, Sophie Zinn-Justin, Francois-Xavier Theillet","doi":"10.1080/19420862.2026.2685366","DOIUrl":"10.1080/19420862.2026.2685366","url":null,"abstract":"<p><p>High-concentration formulations of monoclonal antibodies (mAbs) are required for subcutaneous administration but are frequently challenging to develop due to elevated viscosity and colloidal instability. These properties are governed by mAb-mAb interactions that are regulated by additional mAb-excipient interactions. These ultra-weak interactions remain difficult to characterize using conventional techniques. Here, we combined nuclear magnetic resonance (NMR) spectroscopy with rheometry and dynamic light scattering to investigate mAb interactions under formulation-relevant conditions. Rheological measurements showed that, in the case of the chosen mAb, the excipients arginine and lysine strongly reduce the macroscopic viscosity, whereas other excipients display a moderate effect by themselves. Characterization of the mAb oligomeric state by ¹H NMR confirmed that arginine and lysine are the most efficient at reducing mAb self-assembly, while proline and glycine promote clustering. Interactions between mAb and excipients were first analyzed by measuring excipient diffusion coefficients, but these are only weakly affected by the addition of concentrated mAb. The mAb-excipient interactions were further detected by measuring excipient ¹H and ¹³C chemical shifts, mAb-excipient saturation transfers, and excipient ¹H transverse relaxation rates. These experiments provided complementary information on excipient interactions with the different mAb oligomers. Lysine was identified as the best mAb binder. However, several excipients such as sucrose that do not reduce the macroscopic viscosity also bind to concentrated mAb, highlighting that excipient binding can have various consequences on the transient interactions between mAb species. Altogether, this work proposes a powerful NMR pipeline to dissect ultra-weak molecular interactions that govern viscosity and developability in therapeutic antibody formulations.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2685366"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13271275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148218337","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}

{"title":"Impact of process parameters on IgG glycosylation in CHO systems: a comprehensive quantitative analysis.","authors":"Javier Bravo-Venegas, Jose Rodriguez-Siza, Mauricio Vergara, Mauro Torres, Alan Dickson, Jorge R Toledo, María Carmen Molina, Marcela A Hermoso, Julio Berríos, Claudia Altamirano","doi":"10.1080/19420862.2026.2643039","DOIUrl":"10.1080/19420862.2026.2643039","url":null,"abstract":"<p><p>Controlling glycosylation, a critical quality attribute of biopharmaceuticals such as monoclonal antibodies, is essential, as it significantly influences biological activity and therapeutic efficacy. Although numerous studies have examined the impact of process parameters (PP, e.g. temperature, pH, dissolved oxygen) on glycosylation, the lack of standardized reporting makes cross-study comparisons challenging and prevents clear conclusions. Here, we systematically reviewed the literature and applied a normalized quantitative framework, the Glycan Indices approach, as a standardized quantitative criterion to evaluate the impact of process parameters on glycoform distribution in IgG-producing CHO cell systems objectively. This methodology enabled the integration and reinterpretation of large, heterogeneous datasets, validating some well-known patterns while providing novel perspectives about process parameters. Our analysis revealed that PP manipulations of pH, dissolved oxygen or CO₂ partial pressure rarely resulted in meaningful shifts in glycosylation, with changes <5% observed for galactose, fucose, or N-acetylneuraminic acid content. In contrast, for several cases temperature and osmolality changes notably affected galactosylation (>10%) and fucosylation (1-10%), variations that may have significant biological consequences. To our knowledge, this is the first comprehensive quantitative assessment of process parameters effects on glycosylation, showing that such influences are consistently limited, independent of CHO cell line or culture mode. Based in our observations we strongly recommend reporting both glycan distribution and glycan indices when performing glycan analysis. Dual reporting facilitates inter-study comparisons and prevents subtle shifts in sugar moieties from being masked by glycan redistribution.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2643039"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12990948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147463695","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}

{"title":"Targeting IL-7Rα with PNU-159682 antibody-drug conjugates in acute lymphoblastic leukemia: translational implications.","authors":"Shiqi Yang, Takahiro Anzai, Ryo Tsumura, Hirobumi Fuchigami, Motochika Hamada, Junichiro Yuda, Koichi Ikuta, Masahiro Yasunaga","doi":"10.1080/19420862.2026.2663639","DOIUrl":"10.1080/19420862.2026.2663639","url":null,"abstract":"<p><p>Relapsed acute lymphoblastic leukemia (ALL), particularly with central nervous system (CNS) involvement, remains a major cause of treatment failure and is inadequately controlled by existing antibody-drug conjugates (ADCs) with tubulin inhibitors. To address this limitation, we developed IL-7Rα-targeted monoclonal antibodies and identified clone 577 as the lead candidate. Using this antibody, we generated ADCs conjugated with either monomethyl auristatin E (MMAE) or the highly potent DNA-damaging payload-PNU-159682 (PNU). In head-to-head comparisons, 577-PNU showed >50-fold greater potency than 577-MMAE in vitro and induced complete tumor regression in xenografts at a 20-fold lower dose. Additionally, 577-PNU provided durable systemic disease control and markedly reduced leukemic infiltration in the brain and spinal cord in both preventive and established murine CNS disease models, offering direct evidence of effective CNS penetration. Safety assessments demonstrated stable body weight, normal hematology and serum biochemistry, and no treatment-related pathologies. Collectively, these findings provide the first preclinical evidence that IL-7Rα-directed ADCs armed with DNA-targeting payload PNU-159682 can achieve durable elimination of systemic and CNS leukemia at tolerable doses, demonstrating both clinical feasibility and CNS disease control, and establishing a compelling rationale for their translational and clinical development in relapsed and refractory ALL.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2663639"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775773","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}

{"title":"High-throughput small-angle X-ray scattering reveals effective structure factor transitions linked to high-concentration antibody viscosity.","authors":"Lateefat Kalejaye, I-En Wu, Jia-Min Chu, Mitali Shah, Maria Monica Castellanos, Shirish Chodankar, Neil Mody, Pin-Kuang Lai","doi":"10.1080/19420862.2026.2677285","DOIUrl":"10.1080/19420862.2026.2677285","url":null,"abstract":"<p><p>High-concentration monoclonal antibody (mAb) formulations are often constrained by elevated viscosity, largely driven by protein-protein interactions, which complicates manufacturing and limits subcutaneous delivery. Early viscosity risk assessment is essential during discovery, yet traditional measurements require large sample volumes, and lack high-throughput capability. Here, we develop a high-throughput small-angle X-ray scattering (SAXS) protocol to detect mAb self-association at dilute concentrations, enabling early predictive insights into high-concentration viscosity. Synchrotron SAXS measurements were conducted for 21 mAbs formulated in a histidine buffer at pH 6.0. An initial subset of 10 mAbs analyzed across 1-150 mg/mL revealed that effective structure factor transitions in the low-q region, indicative of interparticle interactions, consistently emerged below 25 mg/mL. Subsequently, 11 additional mAbs were analyzed at 1-25 mg/mL using automated liquid handling and flow cells to enable high-throughput screening. High-viscosity mAbs exhibited detectable low-q upturns at concentrations ≤10 mg/mL, whereas low-viscosity mAbs showed downturns. A classification criterion based on effective structure factor transitions accurately classified all high- and low-viscosity mAbs at 150 mg/mL, offering a scalable, sample-efficient alternative to conventional methods. These results extend recent findings on the concentration-dependent sensitivity of SAXS to short-range attractions, demonstrating that they can emerge at lower concentrations than previously reported. This study presents the most comprehensive and diverse SAXS dataset for mAbs reported to date within a single formulation, providing a valuable resource for developing and validating coarse-grained models that can more accurately capture intermolecular interactions governing high-concentration solution behavior, thereby enabling rational antibody engineering and improved developability.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2677285"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13217917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148031971","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}

{"title":"Structure-based calculation of excipient effects on the viscosity of concentrated antibody solutions.","authors":"John C Shelley, Qing Chai, Lina Wu, Shaghayegh Vafaei, Mee Y Shelley, Eric Feyfant, Jiangyan Feng, Mahlet A Woldeyes, Volodymyr Babin, Jonathan D Jou","doi":"10.1080/19420862.2026.2645310","DOIUrl":"10.1080/19420862.2026.2645310","url":null,"abstract":"<p><p>Computational prediction of the viscosity of therapeutic monoclonal antibodies (mAbs) at high concentration is highly desirable in the early discovery and development phases where the material needed for experimental determination is typically limited. Here, we present a unique coarse-grained (CG) simulation method that enables residue-level simulation of full-length antibodies with an elastic network, under simulated shearing force, to <i>de novo</i> predict viscosities of solutions of two distinct mAbs (an IgG1 and an IgG4), in the absence and presence of six excipients. Our results suggest the method can properly distinguish the viscosity profile of the two model mAbs, and directionally forecast viscosity change in response to added excipients. Furthermore, this CG modeling approach provides detailed protein-protein interaction mapping down to residue-level contacts, including contact lifetimes and nature of interactions, illuminating microscopic insights into the underlying molecular interactions. It serves as a valuable tool for viscosity prediction, mechanistic insights, and mitigation strategies.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2645310"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493923","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}

{"title":"Tokenizing loops of antibodies.","authors":"Ada Fang, Robert G Alberstein, Simon Kelow, Frédéric A Dreyer","doi":"10.1080/19420862.2026.2645271","DOIUrl":"10.1080/19420862.2026.2645271","url":null,"abstract":"<p><p>The complementarity-determining regions (CDRs) of antibodies are loop structures that are key to their interactions with antigens and are of high importance to the design of novel biologics. Existing approaches for characterizing the diversity of CDRs have limited coverage and cannot be readily incorporated into protein foundation models. Here we introduce ImmunoGlobulin LOOp Tokenizer, Igloo, a multimodal antibody loop tokenizer that encodes backbone dihedral angles and sequence. Igloo is trained using a contrastive learning objective to map loops with similar backbone dihedral angles closer together in latent space. Compared to state-of-the-art protein encoding approaches, Igloo can efficiently retrieve the closest matching loop structures from a structural antibody database, outperforming the existing methods on identifying similar H3 loops by 6.1%. Igloo assigns tokens to all loops, addressing the limited coverage issue of canonical clusters, while retaining the ability to recover canonical loop conformations. To demonstrate the versatility of Igloo tokens, we show that they can be incorporated into protein language models with IglooLM and IglooALM. On predicting binding affinity of heavy chain variants, IglooLM outperforms the base protein language model on 8 out of 10 antibody-antigen targets. Additionally, it is on par with existing state-of-the-art sequence-based and multimodal protein language models, performing comparably to models with <math><mn>7</mn><mo>×</mo></math> more parameters. IglooALM samples antibody loops which are diverse in sequence and more consistent in structure than state-of-the-art antibody inverse folding models. We show that Igloo can rapidly and scalably prioritize functional antibody variants from large mutagenesis libraries, achieving a <math><mn>1.9</mn><mo>×</mo></math> enrichment of experimentally validated HER2 binders in a zero-shot setting. Igloo demonstrates the benefit of introducing multimodal tokens for antibody loops for encoding their diverse landscape, improving protein foundation models, and for antibody CDR design.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2645271"},"PeriodicalIF":7.9,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13051602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623193","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}