{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:55:09Z","timestamp":1793228109100,"version":"4.5.0"},"reference-count":105,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]},{"name":"GSO canc\u00e9ropole","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100014808","name":"GEFLUC","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100014808","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FUI13 UmAbHER3 program (BPI France)","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"SIRIC Montpellier Cancer","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"LabEx MAbImprove ANR-10-LABX-53-01","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/501100015760","name":"Inserm Transfert","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100015760","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Monoclonal antibodies have revolutionized the treatment of many diseases, but their clinical efficacy remains limited in some other cases. Pre-clinical and clinical trials have shown that combinations of antibodies that bind to the same target (homo-combinations) or to different targets (hetero-combinations) to mimic the polyclonal humoral immune response improve their therapeutic effects in cancer. The approval of the trastuzumab\/pertuzumab combination for breast cancer and then of the ipilimumab\/nivolumab combination for melanoma opened the way to novel antibody combinations or oligoclonal antibody mixtures as more effective biologics for cancer management. We found more than 300 phase II\/III clinical trials on antibody combinations, with\/without chemotherapy, radiotherapy, small molecules or vaccines, in the ClinicalTrials.gov database. Such combinations enhance the biological responses and bypass the resistance mechanisms observed with antibody monotherapy. Usually, such antibody combinations are administered sequentially as separate formulations. Combined formulations have also been developed in which separately produced antibodies are mixed before administration or are produced simultaneously in a single cell line or a single batch of different cell lines as a polyclonal master cell bank. The regulation, toxicity and injection sequence of these oligoclonal antibody mixtures still need to be addressed in order to optimize their delivery and their therapeutic effects.<\/jats:p>","DOI":"10.3390\/cancers13184620","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T12:00:44Z","timestamp":1631707244000},"page":"4620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Improving Biologics\u2019 Effectiveness in Clinical Oncology: From the Combination of Two Monoclonal Antibodies to Oligoclonal Antibody Mixtures"],"prefix":"10.3390","volume":"13","author":[{"given":"Christel","family":"Larbouret","sequence":"first","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier (IRCM), Institut R\u00e9gional du Cancer de Montpellier (ICM), Inserm U1194, Universit\u00e9 de Montpellier, 34298 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Gros","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier (IRCM), Institut R\u00e9gional du Cancer de Montpellier (ICM), Inserm U1194, Universit\u00e9 de Montpellier, 34298 Montpellier, France"},{"name":"Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9254-2648","authenticated-orcid":false,"given":"Andr\u00e9","family":"P\u00e8legrin","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier (IRCM), Institut R\u00e9gional du Cancer de Montpellier (ICM), Inserm U1194, Universit\u00e9 de Montpellier, 34298 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1836-7439","authenticated-orcid":false,"given":"Thierry","family":"Chard\u00e8s","sequence":"additional","affiliation":[{"name":"Institut de Recherche en Canc\u00e9rologie de Montpellier (IRCM), Institut R\u00e9gional du Cancer de Montpellier (ICM), Inserm U1194, Universit\u00e9 de Montpellier, 34298 Montpellier, France"},{"name":"Centre National de la Recherche Scientifique (CNRS), 75016 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1073\/pnas.0409610102","article-title":"Synergistic Down-Regulation of Receptor Tyrosine Kinases by Combinations of MAbs: Implications for Cancer Immunotherapy","volume":"102","author":"Friedman","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1158\/1078-0432.CCR-04-2653","article-title":"Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor-Specific Antibody Generates Enhanced Antitumor Activity","volume":"11","author":"Perera","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13252","DOI":"10.1073\/pnas.0913476107","article-title":"Combination Antibody Treatment Down-Regulates Epidermal Growth Factor Receptor by Inhibiting Endosomal Recycling","volume":"107","author":"Spangler","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1073\/pnas.1220763110","article-title":"Inhibition of Triple-Negative Breast Cancer Models by Combinations of Antibodies to EGFR","volume":"110","author":"Ferraro","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45432","DOI":"10.18632\/oncotarget.17139","article-title":"ADCC Responses and Blocking of EGFR-Mediated Signaling and Cell Growth by Combining the Anti-EGFR Antibodies Imgatuzumab and Cetuximab in NSCLC Cells","volume":"8","author":"Kol","year":"2017","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1073\/pnas.0812059106","article-title":"Persistent Elimination of ErbB-2\/HER2-Overexpressing Tumors Using Combinations of Monoclonal Antibodies: Relevance of Receptor Endocytosis","volume":"106","author":"Schechter","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","first-page":"273","article-title":"Monoclonal Antibodies Reactive with Distinct Domains of the Neu Oncogene-Encoded P185 Molecule Exert Synergistic Anti-Tumor Effects in Vivo","volume":"2","author":"Drebin","year":"1988","journal-title":"Oncogene"},{"key":"ref_8","first-page":"2771","article-title":"Therapy of an Animal Model of Human Gastric Cancer Using a Combination of Anti-ErbB-2 Monoclonal Antibodies","volume":"52","author":"Kasprzyk","year":"1992","journal-title":"Cancer Res."},{"key":"ref_9","first-page":"1720","article-title":"Targeting Multiple Her-2 Epitopes with Monoclonal Antibodies Results in Improved Antigrowth Activity of a Human Breast Cancer Cell Line in Vitro and in Vivo","volume":"8","author":"Spiridon","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1158\/1078-0432.CCR-17-0782","article-title":"Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors","volume":"23","author":"Poulsen","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1158\/1535-7163.MCT-17-0374","article-title":"Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms","volume":"16","author":"Grandal","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/1476-4598-13-242","article-title":"Overcoming Acquired Resistance to Cetuximab by Dual Targeting HER Family Receptors with Antibody-Based Therapy","volume":"13","author":"Iida","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1158\/1535-7163.MCT-17-0787","article-title":"Acquired Resistance to a MET Antibody In Vivo Can Be Overcome by the MET Antibody Mixture Sym015","volume":"17","author":"Pollmann","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"324ra14","DOI":"10.1126\/scitranslmed.aad5640","article-title":"MM-151 Overcomes Acquired Resistance to Cetuximab and Panitumumab in Colorectal Cancers Harboring EGFR Extracellular Domain Mutations","volume":"8","author":"Arena","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zahavi, D., and Weiner, L. (2020). Monoclonal Antibodies in Cancer Therapy. 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Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1593\/neo.111602","article-title":"In Pancreatic Carcinoma, Dual EGFR\/HER2 Targeting with Cetuximab\/Trastuzumab Is More Effective than Treatment with Trastuzumab\/Erlotinib or Lapatinib Alone: Implication of Receptors\u2019 down-Regulation and Dimers\u2019 Disruption","volume":"14","author":"Larbouret","year":"2012","journal-title":"Neoplasia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7138","DOI":"10.18632\/oncotarget.2231","article-title":"HER3 as Biomarker and Therapeutic Target in Pancreatic Cancer: New Insights in Pertuzumab Therapy in Preclinical Models","volume":"5","author":"Thomas","year":"2014","journal-title":"Oncotarget"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15389","DOI":"10.1073\/pnas.1313857110","article-title":"Inhibition of Pancreatic Carcinoma by Homo- and Heterocombinations of Antibodies against EGF-Receptor and Its Kin HER2\/ErbB-2","volume":"110","author":"Maron","year":"2013","journal-title":"Proc. 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Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12796","DOI":"10.18632\/oncotarget.3473","article-title":"Dual Targeting of HER1\/EGFR and HER2 with Cetuximab and Trastuzumab in Patients with Metastatic Pancreatic Cancer after Gemcitabine Failure: Results of the \u201cTHERAPY\u201dPhase 1-2 Trial","volume":"6","author":"Assenat","year":"2015","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Romaniello, D., Marrocco, I., Belugali Nataraj, N., Ferrer, I., Drago-Garcia, D., Vaknin, I., Oren, R., Lindzen, M., Ghosh, S., and Kreitman, M. (2020). Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor. Cancers, 12.","DOI":"10.3390\/cancers12092394"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.1158\/1078-0432.CCR-13-2752","article-title":"Randomized Phase Ib\/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-Type KRAS Metastatic Colorectal Cancer","volume":"20","author":"Eng","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1200\/JCO.2008.19.8135","article-title":"A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared with Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer","volume":"27","author":"Hecht","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1200\/JCO.2012.44.7912","article-title":"AVEREL: A Randomized Phase III Trial Evaluating Bevacizumab in Combination with Docetaxel and Trastuzumab as First-Line Therapy for HER2-Positive Locally Recurrent\/Metastatic Breast Cancer","volume":"31","author":"Gianni","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"294","DOI":"10.15252\/emmm.201708076","article-title":"An Oligoclonal Antibody Durably Overcomes Resistance of Lung Cancer to Third-Generation EGFR Inhibitors","volume":"10","author":"Mancini","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"ra53","DOI":"10.1126\/scisignal.aaa0725","article-title":"Combining Three Antibodies Nullifies Feedback-Mediated Resistance to Erlotinib in Lung Cancer","volume":"8","author":"Mancini","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1158\/1078-0432.CCR-14-3312","article-title":"Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity","volume":"21","author":"Jacobsen","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/jnci\/djx065","article-title":"An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression","volume":"109","author":"Schwarz","year":"2017","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1914883","DOI":"10.1080\/19420862.2021.1914883","article-title":"Anti-Tumoral Activity of the Pan-HER (Sym013) Antibody Mixture in Gemcitabine-Resistant Pancreatic Cancer Models","volume":"13","author":"Rabia","year":"2021","journal-title":"MAbs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3880","DOI":"10.1200\/JCO.2006.05.6291","article-title":"Multicenter Phase II Trial of Immunotherapy with the Humanized Anti-CD22 Antibody, Epratuzumab, in Combination with Rituximab, in Refractory or Recurrent Non-Hodgkin\u2019s Lymphoma","volume":"24","author":"Strauss","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4275","DOI":"10.1073\/pnas.0915174107","article-title":"PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells within B16 Melanoma Tumors","volume":"107","author":"Curran","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1158\/2326-6066.CIR-14-0118","article-title":"Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector\/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model","volume":"3","author":"Chen","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/1479-5876-11-215","article-title":"Combined TIM-3 Blockade and CD137 Activation Affords the Long-Term Protection in a Murine Model of Ovarian Cancer","volume":"11","author":"Guo","year":"2013","journal-title":"J. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.canlet.2018.05.009","article-title":"Trastuzumab Upregulates PD-L1 as a Potential Mechanism of Trastuzumab Resistance through Engagement of Immune Effector Cells and Stimulation of IFN\u03b3 Secretion","volume":"430","author":"Chaganty","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1158\/1535-7163.MCT-17-0749","article-title":"A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model","volume":"17","author":"Iwata","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5561","DOI":"10.1158\/0008-5472.CAN-13-3622-T","article-title":"Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells","volume":"74","author":"Junttila","year":"2014","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e1353857","DOI":"10.1080\/2162402X.2017.1353857","article-title":"PD-1 Blockade at the Time of Tumor Escape Potentiates the Immune-Mediated Antitumor Effects of a Melanoma-Targeting Monoclonal Antibody","volume":"6","author":"They","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1158\/1078-0432.CCR-16-0040","article-title":"CTLA-4 Limits Anti-CD20-Mediated Tumor Regression","volume":"23","author":"Ren","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/mt.2012.184","article-title":"Cetuximab-Mediated Tumor Regression Depends on Innate and Adaptive Immune Responses","volume":"21","author":"Yang","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1158\/1078-0432.CCR-12-2522","article-title":"Effective Anti-Neu-Initiated Antitumor Responses Require the Complex Role of CD4+ T Cells","volume":"19","author":"Mortenson","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e955684","DOI":"10.4161\/21624011.2014.955684","article-title":"Tumor Antigen-Targeting Monoclonal Antibody-Based Immunotherapy: Orchestrating Combined Strategies for the Development of Long-Term Antitumor Immunity","volume":"3","author":"Michaud","year":"2014","journal-title":"Oncoimmunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.cell.2015.04.016","article-title":"Differential Fc-Receptor Engagement Drives an Anti-Tumor Vaccinal Effect","volume":"161","author":"DiLillo","year":"2015","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"66","DOI":"10.18632\/oncotarget.27868","article-title":"Improved Therapeutic Efficacy of Unmodified Anti-Tumor Antibodies by Immune Checkpoint Blockade and Kinase Targeted Therapy in Mouse Models of Melanoma","volume":"12","author":"Erjavec","year":"2021","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/cei.12069","article-title":"Simultaneous Blockade of Programmed Death 1 and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Induces Synergistic Anti-Tumour Effect in Vivo","volume":"172","author":"Yasuda","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1126\/scitranslmed.aak9679","article-title":"Combined Antiangiogenic and Anti-PD-L1 Therapy Stimulates Tumor Immunity through HEV Formation","volume":"9","author":"Allen","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1158\/1078-0432.CCR-16-0879","article-title":"CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer","volume":"23","author":"Srivastava","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4270","DOI":"10.1158\/0008-5472.CAN-17-2176","article-title":"Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer","volume":"78","author":"Meder","year":"2018","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7142","DOI":"10.1073\/pnas.1016569108","article-title":"Anti-ErbB-2 MAb Therapy Requires Type I and II Interferons and Synergizes with Anti-PD-1 or Anti-CD137 MAb Therapy","volume":"108","author":"Stagg","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Liu, J., Wang, L., Zhao, F., Tseng, S., Narayanan, C., Shura, L., Willingham, S., Howard, M., Prohaska, S., and Volkmer, J. (2015). Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137345"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4464","DOI":"10.1073\/pnas.1600007113","article-title":"Identification of Tumorigenic Cells and Therapeutic Targets in Pancreatic Neuroendocrine Tumors","volume":"113","author":"Krampitz","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Delou, J.M.A., Souza, A.S.O., Souza, L.C.M., and Borges, H.L. (2019). Highlights in Resistance Mechanism Pathways for Combination Therapy. Cells, 8.","DOI":"10.3390\/cells8091013"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa1113216","article-title":"Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1470-2045(11)70336-9","article-title":"Efficacy and Safety of Neoadjuvant Pertuzumab and Trastuzumab in Women with Locally Advanced, Inflammatory, or Early HER2-Positive Breast Cancer (NeoSphere): A Randomised Multicentre, Open-Label, Phase 2 Trial","volume":"13","author":"Gianni","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1703643","article-title":"Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer","volume":"377","author":"Procter","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S1470-2045(20)30536-2","article-title":"Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection plus Chemotherapy in HER2-Positive Early Breast Cancer (FeDeriCa): A Randomised, Open-Label, Multicentre, Non-Inferiority, Phase 3 Study","volume":"22","author":"Tan","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s10549-021-06145-3","article-title":"Subcutaneous Trastuzumab with Pertuzumab and Docetaxel in HER2-Positive Metastatic Breast Cancer: Final Analysis of MetaPHER, a Phase IIIb Single-Arm Safety Study","volume":"187","author":"Kuemmel","year":"2021","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/S1470-2045(18)30481-9","article-title":"Pertuzumab plus Trastuzumab and Chemotherapy for HER2-Positive Metastatic Gastric or Gastro-Oesophageal Junction Cancer (JACOB): Final Analysis of a Double-Blind, Randomised, Placebo-Controlled Phase 3 Study","volume":"19","author":"Tabernero","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1056\/NEJMoa0808268","article-title":"Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer","volume":"360","author":"Tol","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4249","DOI":"10.1021\/mp500460g","article-title":"Cetuximab Reduces the Accumulation of Radiolabeled Bevacizumab in Cancer Xenografts without Decreasing VEGF Expression","volume":"11","author":"Heskamp","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/ijc.28046","article-title":"Bevacizumab Reduces Tumor Targeting of Antiepidermal Growth Factor and Anti-Insulin-like Growth Factor 1 Receptor Antibodies","volume":"133","author":"Heskamp","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab plus Ipilimumab in Advanced Melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMoa1709684","article-title":"Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"377","author":"Wolchok","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1056\/NEJMoa1716948","article-title":"Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC","volume":"378","author":"Socinski","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S1470-2045(18)30812-X","article-title":"Pembrolizumab plus Trastuzumab in Trastuzumab-Resistant, Advanced, HER2-Positive Breast Cancer (PANACEA): A Single-Arm, Multicentre, Phase 1b-2 Trial","volume":"20","author":"Loi","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/S1470-2045(18)30700-9","article-title":"Nivolumab plus Ipilimumab or Nivolumab Alone versus Ipilimumab Alone in Advanced Melanoma (CheckMate 067): 4-Year Outcomes of a Multicentre, Randomised, Phase 3 Trial","volume":"19","author":"Hodi","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4871","DOI":"10.2147\/CMAR.S202017","article-title":"Ipilimumab and Nivolumab as First-Line Treatment of Patients with Renal Cell Carcinoma: The Evidence to Date","volume":"12","author":"Sheng","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1200\/JCO.2017.76.9901","article-title":"Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient\/Microsatellite Instability-High Metastatic Colorectal Cancer","volume":"36","author":"Overman","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_72","first-page":"CD013257","article-title":"Single or Combined Immune Checkpoint Inhibitors Compared to First-Line Platinum-Based Chemotherapy with or without Bevacizumab for People with Advanced Non-Small Cell Lung Cancer","volume":"4","author":"Ferrara","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-4939-8958-4_2","article-title":"Cancer Immunotherapy: The Dawn of Antibody Cocktails","volume":"1904","author":"Marrocco","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.7150\/thno.52614","article-title":"The Current Landscape of Antibody-Based Therapies in Solid Malignancies","volume":"11","author":"Shah","year":"2021","journal-title":"Theranostics"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.ctrv.2015.10.008","article-title":"The Use of Combinations of Monoclonal Antibodies in Clinical Oncology","volume":"41","author":"Henricks","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40425-018-0349-3","article-title":"Current Landscape and Future of Dual Anti-CTLA4 and PD-1\/PD-L1 Blockade Immunotherapy in Cancer; Lessons Learned from Clinical Trials with Melanoma and Non-Small Cell Lung Cancer (NSCLC)","volume":"6","author":"Chae","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1158\/0008-5472.CAN-09-1417","article-title":"Sym004: A Novel Synergistic Anti-Epidermal Growth Factor Receptor Antibody Mixture with Superior Anticancer Efficacy","volume":"70","author":"Pedersen","year":"2010","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10928-019-09663-2","article-title":"Population Pharmacokinetics and Covariate Analysis of Sym004, an Antibody Mixture against the Epidermal Growth Factor Receptor, in Subjects with Metastatic Colorectal Cancer and Other Solid Tumors","volume":"47","author":"Alifrangis","year":"2020","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41598-019-57153-9","article-title":"Targeting of EGFR by a Combination of Antibodies Mediates Unconventional EGFR Trafficking and Degradation","volume":"10","author":"Jones","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"82773","DOI":"10.18632\/oncotarget.19797","article-title":"Antitumor Efficacy of Triple Monoclonal Antibody Inhibition of Epidermal Growth Factor Receptor (EGFR) with MM151 in EGFR-Dependent and in Cetuximab-Resistant Human Colorectal Cancer Cells","volume":"8","author":"Napolitano","year":"2017","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1158\/1535-7163.MCT-14-0772","article-title":"Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic","volume":"14","author":"Kearns","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.1128\/AAC.02830-14","article-title":"Safety and Pharmacokinetics of XOMA 3AB, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin A","volume":"58","author":"Nayak","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1021\/acs.molpharmaceut.0c00370","article-title":"Biophysical Characterization of Binary Therapeutic Monoclonal Antibody Mixtures","volume":"17","author":"Krieg","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1002\/bit.22763","article-title":"Generation of Stable Cell Clones Expressing Mixtures of Human Antibodies","volume":"106","author":"Kramer","year":"2010","journal-title":"Biotechnol. Bioeng."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.tibtech.2007.07.005","article-title":"Antibody Cocktails: Next-Generation Biopharmaceuticals with Improved Potency","volume":"25","author":"Logtenberg","year":"2007","journal-title":"Trends Biotechnol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.ccell.2018.04.003","article-title":"Unbiased Combinatorial Screening Identifies a Bispecific IgG1 That Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade","volume":"33","author":"Geuijen","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"14706","DOI":"10.1074\/jbc.M117.793497","article-title":"A New Approach for Generating Bispecific Antibodies Based on a Common Light Chain Format and the Stable Architecture of Human Immunoglobulin G1","volume":"292","author":"Hendriks","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1080\/14712598.2019.1623200","article-title":"MCLA-117, a CLEC12AxCD3 Bispecific Antibody Targeting a Leukaemic Stem Cell Antigen, Induces T Cell-Mediated AML Blast Lysis","volume":"19","author":"Hangalapura","year":"2019","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Rasmussen, S.K., Nielsen, L.S., M\u00fcller, C., Bouquin, T., N\u00e6sted, H., M\u00f8nster, N.T., Nygaard, F., Weilguny, D., Frandsen, T.P., and Tolstrup, A.B. (2011). Recombinant Antibody Mixtures; Optimization of Cell Line Generation and Single-Batch Manufacturing Processes. BMC Proc., 5.","DOI":"10.1186\/1753-6561-5-S8-O2"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/bit.20865","article-title":"Production of Target-Specific Recombinant Human Polyclonal Antibodies in Mammalian Cells","volume":"94","author":"Wiberg","year":"2006","journal-title":"Biotechnol. Bioeng."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1158\/1078-0432.CCR-15-1664","article-title":"Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models","volume":"22","author":"Francis","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1002\/ijc.30242","article-title":"Pan-HER-An Antibody Mixture Targeting EGFR, HER2 and HER3 Abrogates Preformed and Ligand-Induced EGFR Homo- and Heterodimers","volume":"139","author":"Ellebaek","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13058-020-01280-z","article-title":"Simultaneous Targeting of HER Family Pro-Survival Signaling with Pan-HER Antibody Mixture Is Highly Effective in TNBC: A Preclinical Trial with PDXs","volume":"22","author":"Reddy","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Boune, S., Hu, P., Epstein, A.L., and Khawli, L.A. (2020). Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations. Antibodies, 9.","DOI":"10.3390\/antib9020022"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1080\/07388551.2020.1869684","article-title":"Characterization of Glycosylation in Monoclonal Antibodies and Its Importance in Therapeutic Antibody Development","volume":"41","author":"Kaur","year":"2021","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_96","first-page":"265","article-title":"Patenting Antibody Combination Therapies","volume":"3","author":"Feng","year":"2020","journal-title":"Antib. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.nbt.2011.03.015","article-title":"Advances in the Production and Downstream Processing of Antibodies","volume":"28","author":"Chon","year":"2011","journal-title":"N. Biotechnol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.abb.2012.07.001","article-title":"Recombinant Antibody Mixtures: Production Strategies and Cost Considerations","volume":"526","author":"Rasmussen","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1111\/cas.13767","article-title":"Phase I Dose-Escalation Trial of Sym004, an Anti-EGFR Antibody Mixture, in Japanese Patients with Advanced Solid Tumors","volume":"109","author":"Kojima","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1200\/jco.2014.32.15_suppl.2518","article-title":"Phase 1 Trial of MM-151, a Novel Oligoclonal Anti-EGFR Antibody Combination in Patients with Refractory Solid Tumors","volume":"32","author":"Lieu","year":"2014","journal-title":"JCO"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.3389\/fimmu.2017.01804","article-title":"New Strategies Using Antibody Combinations to Increase Cancer Treatment Effectiveness","volume":"8","author":"Santamaria","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40425-016-0148-7","article-title":"Phase II Study of Vemurafenib Followed by Ipilimumab in Patients with Previously Untreated BRAF-Mutated Metastatic Melanoma","volume":"4","author":"Amin","year":"2016","journal-title":"J. Immunother. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Tosi, D., P\u00e9rez-Gracia, E., Atis, S., Vi\u00e9, N., Comb\u00e8s, E., Gabanou, M., Larbouret, C., Jarlier, M., Mollevi, C., and Torro, A. (2018). Rational Development of Synergistic Combinations of Chemotherapy and Molecular Targeted Agents for Colorectal Cancer Treatment. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4712-z"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1200\/JCO.2014.58.1082","article-title":"Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies","volume":"33","author":"Tosi","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/bjc.2017.473","article-title":"Strategies for Clinical Development of Monoclonal Antibodies beyond First-in-Human Trials: Tested Doses and Rationale for Dose Selection","volume":"118","author":"Viala","year":"2018","journal-title":"Br. J. 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