Over the past 25 years, antibody therapeutics have emerged as clinically and commercially successful pharmaceuticals, rapidly approaching 100 Food and Drug Administration approvals with combined annual global sales exceeding $100 billion. Nearly half of the marketed antibody therapeutics are used in oncology. These antibody-based cancer therapies can be broken down into three categories based on their different mechanisms of action, i.e., (i) natural properties, (ii) engagement of cytotoxic T cells, and (iii) delivery of cytotoxic payloads. Both natural and engineered properties of the antibody molecule are founded on its highly stable and modular architecture. In this review we provide an overview and outlook of the rapidly evolving landscape of antibody-based cancer therapy.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13:1860476.
Wang LX, Tong X, Li C, Giddens JP, Li T. Glycoengineering of antibodies for modulating functions. Annu Rev Biochem. 2019;88:433–59.
Rajewsky K. Clonal selection and learning in the antibody system. Nature. 1996;381:751–8.
Briney B, Inderbitzin A, Joyce C, Burton DR. Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature. 2019;566:393–7.
Beerli RR, Rader C. Mining human antibody repertoires. MAbs. 2010;2:365–78.
Alfaleh MA, Alsaab HO, Mahmoud AB, Alkayyal AA, Jones ML, Mahler SM, et al. Phage display derived monoclonal antibodies: from bench to bedside. Front Immunol. 2020;11:1986.
Zheng S, Moores S, Jarantow S, Pardinas J, Chiu M, Zhou H, et al. Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody. MAbs. 2016;8:551–61.
Scott DE, Bayly AR, Abell C, Skidmore J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov. 2016;15:533–50.
Brezski RJ, Georgiou G. Immunoglobulin isotype knowledge and application to Fc engineering. Curr Opin Immunol. 2016;40:62–9.
Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-engineering for modulated effector functions-improving antibodies for cancer treatment. Antibodies. 2020;9:64
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.
Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest. 2020;130:51–61.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2017;377:1345–56.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2019;381:1535–46.
Labrijn AF, Janmaat ML, Reichert JM, Parren P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.
Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov. 2018;17:509–27.
Lemery S, Keegan P, Pazdur R, First FDA. Approval agnostic of cancer site—when a biomarker defines the indication. N. Engl J Med. 2017;377:1409–12.
Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111.
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.
Müller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 2015;7:315ra188
Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37.
Feng M, Jiang W, Kim BYS, Zhang CC, Fu YX, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19:568–86.
Clynes RA, Desjarlais JR. Redirected T cell cytotoxicity in cancer therapy. Annu Rev Med. 2019;70:437–50.
Rader C. Bispecific antibodies in cancer immunotherapy. Curr Opin Biotechnol. 2020;65:9–16.
Wu X, Demarest SJ. Building blocks for bispecific and trispecific antibodies. Methods. 2019;154:3–9.
Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs. 2017;9:182–212.
Ellerman D. Bispecific T-cell engagers: towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety. Methods. 2019;154:102–17.
Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U.S.A. 1989;86:10024–8.
June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5.
Sadelain M, Riviere I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545:423–31.
Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020;38:473–88.
Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, et al. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020;367:eaba7365
Srivastava S, Furlan SN, Jaeger-Ruckstuhl CA, Sarvothama M, Berger C, Smythe KS, et al. Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade. Cancer Cell. 2021;39:193–208.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl J Med. 2018;378:439–48.
Daher M, Rezvani K. Outlook for new CAR-based therapies with a focus on CAR NK cells: what lies beyond CAR-engineered T cells in the race against cancer. Cancer Discov. 2021;11:45–58.
Hodgins JJ, Khan ST, Park MM, Auer RC, Ardolino M. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 2019;129:3499–510.
Neri D, Sondel PM. Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol. 2016;40:96–102.
Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–8.
Walsh SJ, Bargh JD, Dannheim FM, Hanby AR, Seki H, Counsell AJ, et al. Site-selective modification strategies in antibody-drug conjugates. Chem Soc Rev. 2021;50:1305–53.
Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17:6398–405.
Mazor R, Pastan I. Immunogenicity of immunotoxins containing pseudomonas exotoxin A: causes, consequences, and mitigation. Front Immunol. 2020;11:1261.
Green DJ, Press OW. Whither radioimmunotherapy: to be or not to be? Cancer Res. 2017;77:2191–6.
Kraeber-Bodere F, Faivre-Chauvet A, Ferrer L, Vuillez JP, Brard PY, Rousseau C, et al. Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial. Clin Cancer Res. 2003;9:3973S–81S.
Kobayashi H, Choyke PL. Near-infrared photoimmunotherapy of cancer. Acc Chem Res. 2019;52:2332–9.
Mitsunaga M, Ogawa M, Kosaka N, Rosenblum LT, Choyke PL, Kobayashi H. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat Med. 2011;17:1685–91.
Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med. 2013;5:207ra144.
Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574:565–70.
Kamata-Sakurai M, Narita Y, Hori Y, Nemoto T, Uchikawa R, Honda M, et al. Antibody to CD137 activated by extracellular adenosine triphosphate is tumor selective and broadly effective in vivo without systemic immune activation. Cancer Discov. 2021;11:158–75.
Denkberg G, Cohen CJ, Lev A, Chames P, Hoogenboom HR, Reiter Y. Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC-restricted T cell receptor-like specificity. Proc Natl Acad Sci U.S.A. 2002;99:9421–6.
Hsiue EH-C, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, et al. Targeting a neoantigen derived from a common TP53 mutation. Science. 2021;371:eabc8697
Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J Am Chem Soc. 2021;143:593–8.
Goydel RS, Weber J, Peng H, Qi J, Soden J, Freeth J, et al. Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications. J Biol Chem. 2020;295:5995–6006.
We acknowledge support by predoctoral stipends from the Klorfine Foundation and the Frenchman’s Creek Women for Cancer Research (to R.S.G.) and National Institutes of Health Grants R01 CA174844, R01 CA181258, R01 CA204484, and R21 CA229961 (to C.R.). We thank Dr. HaJeung Park from the X-Ray Crystallography Core of The Scripps Research Institute (Jupiter, FL) for contributing Fig. 1C.
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Goydel, R.S., Rader, C. Antibody-based cancer therapy. Oncogene 40, 3655–3664 (2021). https://doi.org/10.1038/s41388-021-01811-8