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Here, we investigate the relative contributions of Fab\u2013Fab and Fab\u2013Fc interactions to high concentration viscosity for a diverse panel of 20 IgG\n                    <jats:sub>1<\/jats:sub>\n                    antibodies, by rheometry, coarse-grained simulations, and molecular surface property analysis. Strikingly, fragmentation of IgG\n                    <jats:sub>1<\/jats:sub>\n                    into F(ab\u2032)\n                    <jats:sub>2<\/jats:sub>\n                    plus Fc reduced viscosity (\u221211 to \u221293%) for all antibodies tested, demonstrating prevalent contributions of Fc to viscosity. Coarse-grained simulations with one site per Fab and two sites per Fc qualitatively tracked trends in experimental rheometry data for 20 parental antibodies and their fragments. In these simulations Fab\u2013Fab and Fab\u2013Fc interaction strengths were independently varied to capture possible interaction differences arising from parental sequences or any mutations. These coarse-grained simulations suggest that Fab\u2013Fc attractions generate branched IgG\n                    <jats:sub>1<\/jats:sub>\n                    networks and disproportionately larger clusters relative to Fab\u2013Fab interactions of comparable strength. This study suggests that a four-site self-interaction model, previously proposed for a single antibody (omalizumab), is broadly applicable to diverse IgG\n                    <jats:sub>1<\/jats:sub>\n                    . Beyond well-established variable domain engineering, this self-interaction model predicts that Fc engineering may reduce IgG\n                    <jats:sub>1<\/jats:sub>\n                    viscosity, a much sought after goal to enable subcutaneous delivery. Clinically validated Fc mutations are demonstrated here to substantially reduce the viscosity for multiple IgG\n                    <jats:sub>1<\/jats:sub>\n                    (\u221233 to \u221291% reduction, n = 6), supporting this emerging antibody design concept.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2526550123","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:34:27Z","timestamp":1774373667000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Fab\u2013Fc and Fab\u2013Fab interactions of variable strength and valency contribute to the high concentration viscosity of IgG\n                    <sub>1<\/sub>\n                    antibodies"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-3035","authenticated-orcid":false,"given":"Joel","family":"Heisler","sequence":"first","affiliation":[{"name":"Department of Antibody Engineering, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2799-3172","authenticated-orcid":false,"given":"Jennifer L.","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Department of AI for Drug Discovery, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6491-5806","authenticated-orcid":false,"given":"Zhenyu","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Antibody Engineering, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Zarzar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Development, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4206-8559","authenticated-orcid":false,"given":"Saeed","family":"Izadi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Development, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7854-062X","authenticated-orcid":false,"given":"Paul J.","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Antibody Engineering, Genentech, Inc.","place":["South San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-025-01207-9"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.05.029"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2021.03.017"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2018.01.015"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0232713"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.4161\/19420862.2014.985504"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/mp200566k"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2024.05.041"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2024.2304282"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2024.2379560"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.151.5.2623"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4285"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2021.12.027"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.21322"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2019.1692764"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2016.1222342"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.3c00023"},{"key":"e_1_3_4_18_2","first-page":"262","article-title":"US FDA-approved therapeutic antibodies with high-concentration formulation: Summaries and perspectives","volume":"4","author":"Wang S. 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