{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:16:35Z","timestamp":1788412595973,"version":"build-2803163510"},"reference-count":104,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 CA281962"],"award-info":[{"award-number":["R01 CA281962"]}]},{"name":"NIH","award":["R21 CA282378"],"award-info":[{"award-number":["R21 CA282378"]}]},{"award":["R01 CA281962"],"award-info":[{"award-number":["R01 CA281962"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21 CA282378"],"award-info":[{"award-number":["R21 CA282378"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Jerold B. Katz Endowment in Stem Cell Research"},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences"},{"id":[{"id":"https:\/\/ror.org\/04twxam07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Bispecific antibodies (bsAbs) and bispecific antibody\u2013drug conjugates (bsADCs) represent promising classes of emerging targeted therapeutics with the potential to overcome tumor heterogeneity and resistance in colorectal cancer (CRC). BsAbs can simultaneously engage multiple tumor antigens or immune cells or bind two distinct epitopes within a single target, enabling mechanisms of action beyond the capabilities of monoclonal antibodies. Bispecific T cell engagers facilitate targeted destruction of tumors through immune cell recruitment, while dual immune checkpoint inhibitors enhance immune activation by blocking T cell inhibitory signals. Furthermore, bsAbs can mediate dual signaling pathway inhibition through binding multiple receptor tyrosine kinase receptors or other tumor cell surface proteins. BsADCs integrate the dual-antigen recognition of bsAbs with targeted payload delivery, utilizing receptor-mediated endocytosis to deliver potent cytotoxic payloads selectively to CRC cells, while minimizing systemic toxicity. Recent advances in bsAb engineering, linker chemistry, site-specific conjugation, and payload design have accelerated the development of bsADCs for solid tumors, including CRC. BsAbs and bsADCs provide opportunities to improve tumor selectivity, enhance internalization, overcome antigen escape, and expand the population of CRC patients eligible for targeted therapy. Emerging preclinical studies demonstrate encouraging anti-tumor activity for bispecific modalities in CRC, while early clinical trials are beginning to establish their translational potential. This review summarizes the current landscape of bsAbs and bsADCs in therapeutic development for CRC, highlighting key biological targets, engineering strategies, mechanisms of action, and clinical status. We also discuss the major challenges facing clinical translation and provide perspectives on future directions for bispecific therapies in CRC.<\/jats:p>","DOI":"10.3390\/antib15050080","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:33:32Z","timestamp":1788262412000},"page":"80","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advances in Bispecific Antibodies and Antibody\u2013Drug Conjugates for Colorectal Cancer Treatment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6592-0938","authenticated-orcid":false,"given":"Maya G.","family":"Cappellino","sequence":"first","affiliation":[{"name":"Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1232-2528","authenticated-orcid":false,"given":"Sean P.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-4490","authenticated-orcid":false,"given":"Peyton C.","family":"High","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffani A.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-6096","authenticated-orcid":false,"given":"Kendra S.","family":"Carmon","sequence":"additional","affiliation":[{"name":"Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","first-page":"e70067","article-title":"Colorectal Cancer Statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. 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