Abstract
The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody–drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.
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Data availability
The data used to make Figs. 1 and 6 are available from the American Cancer Society and the Antibody Society.
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Acknowledgements
S.P. M.F.K., C.B., N.P. and S.Z. were supported by The Virginia and D.K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, The Commonwealth Fund, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and the National Institutes of Health (NIH) Cancer Center Support grant P30 CA006973. S.P. was supported by NCI grant K08CA270403, the Leukaemia Lymphoma Society Translation Research Program award, the American Society of Hematology Scholar award, and the Swim Across America Translational Cancer Research Award. M.F.K. was supported by NIH/NIAID grant 1R21AI176764-01, the Jerome Greene Foundation, the Cupid Foundation, the Lupus Research Alliance Lupus Innovation Award, the Rheumatology Research Foundation Investigator Award, the Harrington Discovery Institute Harrington Scholar-Innovator Award, the Sol Goldman MS Research Program, and the Bisciotti Foundation Translational Fund. C.B. was supported by NCI grant R37 CA230400. M.H. was supported by the Intramural Research Program of NIH, NCI and Center for Cancer Research (Z01 BC010891, ZIA BC010891 and ZIC BC 011891).
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S.P., K.M.W., S.B.G. and M.H. researched data for the article. S.P., S.B.G., M.H. and A.vE. contributed substantially to discussion of the content. S.P., K.M.W., S.B.G., M.H., A.vE. and S.Z. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Competing interests
The Johns Hopkins University has filed patent applications related to technologies described in this paper on which S.P., M.F.K., N.P., D.M.P. and S.Z. are listed as inventors. M.H. is an inventor on NIH patents in antibody and cell therapies and may receive blinded royalties from the NIH. N.P. is a founder of Thrive Earlier Detection, an Exact Sciences company. N.P. is a consultant to Thrive Earlier Detection. N.P. and S.Z. hold equity in Exact Sciences. N.P. and S.Z. are founders of and/or consultants to and own equity in ManaT Bio., Neophore and Personal Genome Diagnostics. N.P. holds equity in Haystack Oncology and CAGE Pharma. N.P. is a consultant to Vidium. S.P. owns equity in Gilead, is a consultant to Merck and received payment from IQVIA. M.F.K. is a consultant to Argenx, Atara Biotherapeutics, Revel Pharmaceuticals, Sana Biotechnology and Sanofi. S.Z. has a research agreement with BioMed Valley Discoveries, Inc. C.B. is a consultant for Depuy-Synthes, Bionaut Labs, Galectin Therapeutics, Haystack Oncology and Privo Technologies. C.B. is a co-founder of OrisDx and Belay Diagnostics. D.M.P. reports grant and patent royalties through institution from BMS, a grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder equity from Potenza; is a founder of and consultant to and owns equity in ManaT Bio; is a consultant for Aduro Biotech, Amgen, Astra Zeneca (Medimmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona and Immunomic-Therapeutics; is on the scientific advisory board of Five Prime Therapeutics, Camden Nexus II, WindMil; and is on the board of directors for Dracen Pharmaceuticals. K.M.W. and S.B.G. are employees of Merck & Co., Inc. at the time of submission and may have stock ownership in Merck & Co., Inc., Rahway, NJ, USA.
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Related links
American Cancer Society: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html
Antibody Society: https://www.antibodysociety.org/resources/approved-antibodies/
Supplementary information
Glossary
- Anaphylaxis
-
A severe and potentially life-threatening reaction owing to exposure to an allergen such as an antibody or other medication. Common symptoms of anaphylaxis include swelling of the face and throat, difficulty in breathing, an increase in heart rate, a drop in blood pressure and loss of consciousness.
- Antibody-dependent cellular cytotoxicity
-
(ADCC). A mechanism through which antibodies bind to target cells followed by recruitment of immune cells such as NK cells and macrophages to kill the target cells. The immune cells secrete cytotoxic granules (perforins and granzymes), and induce FAS signalling leading to target cell death.
- Antibody-dependent cellular phagocytosis
-
(ADCP). A mechanism through which antibodies bind to target cells, which in turn stimulates immune cells such as macrophages to engulf and degrade the target cells.
- B cell cloning
-
Isolation and expansion of single B cells that produce the desired monoclonal antibodies, to obtain the antibody-coding sequence.
- Bystander effects
-
With antibody–drug conjugates (ADCs), refers to a phenomenon wherein neighbouring cells near the target cancer cell are killed by the released cytotoxic payload. This effect can enhance the overall potency of the ADC by causing a broader destruction of cancer cells beyond the primary target cell.
- Capillary leak syndrome
-
Condition characterized by the leakage of fluid from small blood vessels (capillaries) into surrounding tissues. This leakage leads to a decrease in blood volume and can result in low blood pressure along with oedema (swelling) in various parts of the body, including the lungs, and organ failure.
- Complementarity-determining regions
-
(CDRs). Specific regions within the antibody heavy and light chain variable domains that bind to the target antigen.
- Complement-dependent cytotoxicity
-
(CDC). A mechanism through which antibodies bind to the target cell followed by activation of the complement system, leading to lysis of the target cells.
- Cytokine release syndrome
-
(CRS). Systemic inflammation characterized by a constellation of symptoms such as fever, hypotension and hypoxia and mediated by the release of multiple cytokines from the immune cells of patients. CRS is a typical adverse effect observed with the use of T cell engager (TCE) bispecific antibodies.
- Cytopenias
-
A reduction in the number of circulating blood cells, such as red blood cells (erythrocytes), white blood cells (leukocytes) and/or platelets (thrombocytes). Cytopenias can be caused by several factors including exposure to drugs or antibodies that hinder the growth of new cells.
- Drug–antibody ratio
-
(DAR). The number of drugs attached to each antibody in an ADC.
- Fragment antigen binding
-
(Fab). An antibody which consists of two identical Fab fragments and one Fc fragment. Each Fab fragment is responsible for binding to a specific antigen. The Fab fragment is obtained by cleaving the antibody at specific sites using enzymes, such as papain or pepsin.
- Fragment crystallizable
-
(Fc). Fc fragment interacts with various immune cells through Fc receptors and with complement proteins that contribute to the immune response generated by the antibody. Each antibody class and subclass has unique Fc regions. Understanding the Fc fragment is crucial in the design of therapeutic antibodies because modifications to this region can impact the pharmacokinetics, effector functions and therapeutic efficacy of an antibody.
- Haemolytic uremic syndrome
-
A rare but serious condition that is characterized by the combination of haemolytic anaemia (destruction of red blood cells), thrombocytopenia (low platelet count) and acute kidney injury. It can be mediated by bacterial infections (such as Escherischia coli) or exposure to drugs and antibodies.
- Hydrophobicity
-
Refers to the property of being repelled by water. Hydrophobic substances are insoluble or poorly soluble in water. The hydrophobicity of the payload can affect the overall stability of the ADC. Highly hydrophobic payloads may lead to aggregation or destabilization of the ADC structure, potentially impacting its efficacy and safety.
- Microsatellite instability-high
-
(MSI-H). Cells with mismatch-repair deficiency resulting in high mutation burden and altered microsatellite (tract of repetitive DNA) sequences. MSI-H cancers are associated with a higher response to immune checkpoint-inhibiting antibodies.
- Monoclonal antibodies
-
Identical antibodies that bind to a specific part of the target antigen (epitope) and are derived from single clones of immune cells (such as B cells, plasma cells or hybridoma cells).
- Myelodysplastic syndromes
-
A group of disorders characterized by abnormal production and maturation of blood cells in the bone marrow. In myelodysplastic syndromes, the bone marrow fails to produce enough healthy blood cells, leading to low levels of red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia).
- Neonatal Fc receptor
-
(FcRn). A receptor expressed by vascular endothelial cells and immune cells, which binds to the Fc portion of IgG antibodies. IgG antibody binding to FcRn leads to receptor-mediated internalization and recycling of the IgG, which is responsible for the long IgG half-life (about 21 days) in circulation.
- Peripheral neuropathy
-
A potential side effect that can occur owing to the cytotoxic payload component of the ADC affecting the peripheral nerves. Peripheral neuropathy caused by ADCs can manifest as numbness, tingling, burning sensations or pain in the hands, feet or other extremities.
- Public neoantigens
-
A public neoantigen is derived from a mutated protein and is found in multiple individuals with the same type of cancer. This shared characteristic makes public neoantigens particularly important in cancer immunotherapy because therapies targeting these common neoantigens can benefit a broad patient population. Common public neoantigens include BRAFV600E, KRASG12D, KRASG12C and TP53R175H. By contrast, private neoantigens are unique to an individual patient with cancer. Targeting private neoantigens requires the development of personalized therapies such as custom cancer vaccines and T cell-based therapies.
- Single-chain variable fragment
-
(scFv). An engineered antibody fragment composed of variable regions of the heavy and light chains combined into a single peptide chain by a linker. The scFv retains the ability to bind specifically to a target antigen, similar to a full-size antibody. The advantages of scFv include its smaller size (~25 kDa), which facilitates easier production and manipulation.
- Single-domain antibodies
-
Also known as nanobodies, are antibodies derived from camelids that consist of only a variable heavy domain and as a result have a relatively low molecular weight (~15 kDa), hence the name nanobody. By contrast, human antibodies consist of variable heavy and light domains and have higher molecular weights (a full-length IgG antibody is ~150 kDa and an scFv is ~ 25 kDa).
- Topoisomerase
-
Enzymes that maintain proper function and stability of DNA by cleaving DNA to relieve torsional strain and supercoiling occurring owing to processes such as DNA replication. Topoisomerase inhibitors disrupt this ability to maintain DNA and cause cell death.
- Tumour antigens
-
Proteins and other antigenic molecules expressed on the surface of tumour cells that can be targeted by therapeutic antibodies.
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Paul, S., Konig, M.F., Pardoll, D.M. et al. Cancer therapy with antibodies. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00690-x
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DOI: https://doi.org/10.1038/s41568-024-00690-x
