@article{tiruthani_cruz-teran_chan_ma_mcsweeney_wolf_yuan_poon_chan_botta_et al._2024, title={Engineering a "muco-trapping" ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19}, ISSN={["2380-6761"]}, DOI={10.1002/btm2.10650}, abstractNote={AbstractSoluble angiotensin‐converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco‐trapping” ACE2‐Fc conjugate, termed ACE2‐(G4S)6‐Fc, comprised of the extracellular segment of ACE2 (lacking the C‐terminal collectrin domain) that is linked to mucin‐binding IgG1‐Fc via an extended glycine‐serine flexible linker. ACE2‐(G4S)6‐Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2‐Fc decoys or similar truncated ACE2‐Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2‐(G4S)6‐Fc effectively trapped fluorescent SARS‐CoV‐2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2‐(G4S)6‐Fc in hamsters as late as 2 days postinfection provided a 10‐fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2‐(G4S)6‐Fc as an inhaled immunotherapy for COVID‐19, as well as other emerging viruses that bind ACE2 for cellular entry.}, journal={BIOENGINEERING & TRANSLATIONAL MEDICINE}, author={Tiruthani, Karthik and Cruz-Teran, Carlos and Chan, Jasper F. W. and Ma, Alice and Mcsweeney, Morgan and Wolf, Whitney and Yuan, Shoufeng and Poon, Vincent K. M. and Chan, Chris C. S. and Botta, Lakshmi and et al.}, year={2024}, month={Feb} }
 @article{mcsweeney_stewart_richardson_kang_park_kim_tiruthani_wolf_schaefer_kumar_et al._2022, title={Stable nebulization and muco-trapping properties of regdanvimab/IN-006 support its development as a potent, dose-saving inhaled therapy for COVID-19}, ISSN={["2380-6761"]}, DOI={10.1002/btm2.10391}, abstractNote={AbstractThe respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID‐19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self‐dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc‐mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID‐19 in several countries, can effectively trap SARS‐CoV‐2 virus‐like particles in fresh human airway mucus. IN‐006, a reformulation of regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN‐006 resulted in 100‐fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN‐006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS‐CoV‐2 and other respiratory pathologies.}, journal={BIOENGINEERING & TRANSLATIONAL MEDICINE}, author={McSweeney, Morgan and Stewart, Ian and Richardson, Zach and Kang, Hyunah and Park, Yoona and Kim, Cheolmin and Tiruthani, Karthik and Wolf, Whitney and Schaefer, Alison and Kumar, Priya and et al.}, year={2022}, month={Aug} }
 @article{shrestha_schaefer_zhu_saada_jacobs_chavez_omsted_cruz-teran_vaca_vincent_et al._2021, title={Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception}, volume={13}, ISSN={["1946-6242"]}, DOI={10.1126/scitranslmed.abd5219}, abstractNote={Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 μg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications.}, number={606}, journal={SCIENCE TRANSLATIONAL MEDICINE}, author={Shrestha, Bhawana and Schaefer, Alison and Zhu, Yong and Saada, Jamal and Jacobs, Timothy M. and Chavez, Elizabeth C. and Omsted, Stuart S. and Cruz-Teran, Carlos A. and Vaca, Gabriela Baldeon and Vincent, Kathleen and et al.}, year={2021}, month={Aug} }
 @article{schaefer_lai_2021, title={The biophysical principles underpinning muco-trapping functions of antibodies}, ISSN={["2164-554X"]}, DOI={10.1080/21645515.2021.1939605}, abstractNote={ABSTRACT In addition to the classical immunological functions such as neutralization, antibody-dependent cellular cytotoxicity, and complement activation, IgG antibodies possess a little-recognized and under-utilized effector function at mucosal surfaces: trapping pathogens in mucus. IgG can potently immobilize pathogens that otherwise readily diffuse or actively swim through mucus by forming multiple low-affinity bonds between the array of pathogen-bound antibodies and the mucin mesh. Trapping in mucus can exclude pathogens from contacting target cells, and facilitate their rapid elimination by natural mucus clearance mechanisms. Despite the fact that most infections are transmitted at mucosal surfaces, this muco-trapping effector function has only been revealed within the past decade, with the evidence to date suggesting that it is a universal effector function of IgG-Fc capable of immobilizing both viral and highly motile bacterial pathogens in all major mucosal secretions. This review provides an overview of the current evidence for Fc-mucin crosslinking as an effector function for antibodies in mucus, the mechanism by which the accumulation of weak Fc-mucin bonds by IgG bound to the surface of a pathogen can result in immobilization of antibody-pathogen complexes, and how trapping in mucus can contribute to protection against foreign pathogens.}, journal={HUMAN VACCINES & IMMUNOTHERAPEUTICS}, author={Schaefer, Alison and Lai, Samuel K.}, year={2021}, month={Jun} }