Cancer therapy with antibodies

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.

Fig. 1 ∣. Antibody components.

a, Antibodies consist of two identical light chains and heavy chains that are held together by disulfide bonds and resemble a Y-shaped structure. Each light and heavy chain contains a variable (V_L and V_H) domain responsible for antigen binding and constant (C_L and C_H) domains that determine the half-life and effector function of the antibody. Enzymatic processing can break up antibodies into two fragments named fragment antigen binding (Fab) and fragment crystallizable (Fc). The light and heavy chain variable regions together make up the fragment variable (Fv), the smallest fragment that retains antigen-binding capacity. Manufactured Fv fragments are joined together by a flexible peptide linker to form a single chain named single-chain variable fragment (scFv). Antibodies are grouped as mouse, chimeric, humanized and human based on the amount of peptide sequence derived from each species. ^aBelantamab mafodotin was withdrawn but may gain re-approval based on ongoing trials. Teclistamab (a combination of a humanized and a human antibody) is considered as a humanized antibody for this figure. CDRs, complementarity-determining regions.

Fig. 2 ∣. Antibody formats and mechanisms of action.

a, On the basis of structure and mechanism of action, therapeutic antibodies can be grouped in three different formats: monospecific antibodies, bispecific antibodies, and drug-conjugated, toxin-conjugated or radioisotope-conjugated antibodies. b, Monospecific antibodies bind antigens on cancer cells leading to cell death by a variety of mechanisms, which include disruption of survival signals from growth factor receptors (such as human epidermal growth factor receptor 2 (HER2)), activation of immune cells (such as natural killer (NK) cell-mediated killing by antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated killing by antibody-dependent cellular phagocytosis (ADCP)), and through activation of the complement cascade (complement-dependent cytotoxicity (CDC)). The immune checkpoint-blocking antibodies bind to and activate immune cells such as T cells leading to immune-mediated cancer cell death. Bispecific antibodies bind two disparate antigens. Most bispecific antibodies are designed to bind T cells (T cell engagers) and cancer cells, and redirect the T cells to kill the cancer cells. The non-T cell-engaging bispecifics bind to two different antigens on the cancer cell surface, leading to direct cancer cell killing. Antibody–drug conjugates (ADCs), immunotoxins and radioisotope-conjugated antibodies carry a toxic payload that enhances the ability of the antibody to kill the cancer cell. BCMA, B cell maturation antigen; EGFR, epidermal growth factor receptor; gp100, glycoprotein 100; GPRC5D, G-protein-coupled receptor family C group 5 member D; FcγR, Fc γ-receptor; PD1, programmed cell death protein 1; PDL1, PD1 ligand 1; scFv, single-chain variable fragment; TCR, T cell receptor.

Fig. 3 ∣. The structural basis of antibody–antigen interactions.

a, Human epidermal growth factor receptor 2 (HER2)-specific antibodies bind different HER2 epitopes. Cryogenic electron microscopy (cryo-EM) structure of the HER2 extracellular domain (ECD) in complex with trastuzumab and pertuzumab fragment antigen binding (Fab) domains (PDB ID: 8Q6J). b, The cryo-EM structure of a CD20 homodimer in complex with two rituximab Fab domains (PDB ID: 6VJA) demonstrates that each CD20 molecule engages a rituximab Fab. Rituximab promotes clustering of CD20 by forming large supramolecular complexes via cross-linking CD20 dimers. c, Programmed cell death protein 1 (PD1)-specific antibodies bind different PD1 epitopes. Both the pembrolizumab Fab (orange and gold; PDB ID: 5GGS) and the nivolumab Fab (magenta and pink; PDB ID: 5GGR) overlap with the PD1 ligand 1 (PDL1) (white) binding site on PD1 (teal), preventing PD1–PDL1 interactions. Surface representations are shown for all protein molecules. d, Alignment of the PD1–PDL2 (PDB ID: 6UMT) and the PDL1 antibody atezolizumab (PDB ID: 5XXY) structures. The structural analysis suggests that the PDL2 residue Trp100 fits in a pocket inside PD1 and aids PD1-PDL2 binding. The same residue in PDL2 (Trp100) perturbs atezolizumab binding to PDL2. e, The complex structures of ipilimumab (PDB ID: 5TRU) and tremelimumab (PDB ID: 5GGV) Fab domains with cytotoxic T lymphocyte-associated antigen 4 (CTLA4) revealed similar binding epitopes that have a large buried surface area effectively outcompeting the binding of the natural ligand, CD80 and CD86. f, The p53(R175H) peptide–major histocompatibility complex (MHC) binding antibody binds parallel to the peptide binding cleft within the MHC molecule (PDB ID: 6W51). By contrast, the p53(R175H)-specific T cell receptor (TCR) binds perpendicular to the peptide binding cleft (PDB ID: 6VQO).

Fig. 4 ∣. The treatment effect of T cells reinvigorated or redirected against cancer cells with immune checkpoint inhibitors or bispecific antibodies.

a,b, Fluorodeoxyglucose (FDG)-positron emission tomography (PET) images (a) and haematoxylin and eosin (H&E)-stained tumour sections (b) from an individual with head and neck squamous cell carcinoma (HNSCC) involving the border of the left side of the tongue. The patient received treatment with the immune checkpoint inhibitors nivolumab and ipilimumab and experienced a substantial reduction in tumour burden. The on-treatment H&E section shows keratinous debris (KD) and surrounding multinucleated giant cells (arrows) and the on-treatment FDG-PET image shows a reduction in FDG uptake at the border of the tongue. c, CT scan of a patient with B cell lymphoma, before and 4 weeks after treatment with the bispecific antibody T cell engager targeting CD19, blinatumomab. This patient had a partial response to blinatumomab. Arrows point to involved lymph node tumours in the mediastinum. d, Bone marrow biopsy sample from another patient with B cell lymphoma before and 15 days after treatment with blinatumomab. Tumour cells are in blue (haematoxylin stain) and T cells are in brown (CD3 stain). Parts a and b are adapted from ref. , Springer Nature. Parts c and d are reprinted with permission from ref. , AAAS.

Fig. 5 ∣. Timeline of the development of bispecific antibodies and conjugated antibodies.

a, Timeline of bispecific antibodies. b, Timeline of drug-conjugated, immunotoxin-conjugated and radioactive isotope-conjugated antibodies. ^aCatumaxomab, an epithelial cell adhesion molecule (EpCAM)xCD3 bispecific antibody, was approved by the European Medicines Agency (EMA) in 2009 for the treatment of malignant ascites but was subsequently withdrawn by the manufacturer for commercial reasons. ADC, antibody–drug conjugate; ALL, acute lymphoblastic leukaemia; B-ALL, B cell precursor acute lymphoblastic leukaemia; BCMA, B cell maturation antigen; AML, acute myeloid leukaemia; CEA, carcinoembryonic antigen; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; gp100, glycoprotein 100; HCL, hairy cell leukaemia; MRD, minimal residual disease; NHL, non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; TCR, T cell receptor.

Fig. 6 ∣. Antibody targets in common solid and haematological cancers.

These graphs show the percentage of deaths from the top 15 cancer types in the USA versus the number of unique antigens being targeted by approved antibodies and antibodies in late-phase clinical trials. The antigen targets are displayed across from each cancer tissue. Note that non-small-cell and small-cell lung cancers are included under ‘Lung’; Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukaemia (CLL) and central nervous system (CNS) lymphoma are included under ‘Lymphoma’; and acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML) and other leukaemias are included under ‘Leukaemia’. Microsatellite instability-high (MSI-H) cancers irrespective of tissue type are eligible for immune checkpoint inhibitor therapy, and HER2-positive solid tumours are eligible for HER2-directed therapy with trastuzumab deruxtecan, and are not included in the analysis. Lutetium Lu 177 vipivotide tetraxetan for prostate cancer was not included because the targeting moiety is not an antibody. Data for the percentage of cancer deaths and the number of approved targets were obtained from the https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html and the Antibody Society, respectively. ^aProgrammed cell death protein 1 (PD1) therapy is approved only in Hodgkin lymphoma. ^bB7-H3 is considered a tumour-associated antigen and a possible immune checkpoint antigen.