Edited by: Rasha Abu Eid, University of Aberdeen, United Kingdom
Reviewed by: Iain James Nixon, National Health Service Scotland, United Kingdom; Sven Brandau, University of Duisburg-Essen, Germany; Marija Kovacevic-Sarmiento, University of Duisburg-Essen, Germany, in collaboration with reviewer SB
*Correspondence: Mohammed M. Al Qaraghuli,
This article was submitted to Head and Neck Cancer, a section of the journal Frontiers in Oncology
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Head and neck cancer (HNC) is a heterogeneous disease that includes a variety of tumors originating in the hypopharynx, oropharynx, lip, oral cavity, nasopharynx, or larynx. HNC is the sixth most common malignancy worldwide and affects thousands of people in terms of incidence and mortality. Various factors can trigger the development of the disease such as smoking, alcohol consumption, and repetitive viral infections. HNC is currently treated by single or multimodality approaches, which are based on surgery, radiotherapy, chemotherapy, and biotherapeutic antibodies. The latter approach will be the focus of this article. There are currently three approved antibodies against HNCs (cetuximab, nivolumab, and pembrolizumab), and 48 antibodies under development. The majority of these antibodies are of humanized (23 antibodies) or human (19 antibodies) origins, and subclass IgG1 represents a total of 32 antibodies. In addition, three antibody drug conjugates (ADCs: telisotuzumab-vedotin, indatuximab-ravtansine, and W0101) and two bispecific antibodies (GBR 1372 and ABL001) have been under development. Despite the remarkable success of antibodies in treating different tumors, success was limited in HNCs. This limitation is attributed to efficacy, resistance, and the appearance of various side effects. However, the efficacy of these antibodies could be enhanced through conjugation to gold nanoparticles (GNPs). These conjugates combine the high specificity of antibodies with unique spectral properties of GNPs to generate a treatment approach known as photothermal therapy. This approach can provide promising outcomes due to the ability of GNPs to convert light into heat, which can specifically destroy cancer cells and treat HNC in an effective manner.
Head and neck cancer (HNC) affects over 830,000 patients worldwide, and about 430,000 people had died from this disease in 2018 (
The most common treatment modalities for HNCs include surgery, radiotherapy (RT), chemotherapy (CT), and biotherapeutic antibodies. Early-stage tumors can be treated with single modality treatment such as surgery or RT (
Various review articles have focused on different treatment options for HNCs such as surgery (
B-lymphocyte cells are instructed by numerous immunogens, such as bacteria, viruses, fungi, parasites, cellular antigens, chemicals, and synthetic substances to differentiate into plasma cells (
Overall structure of IgG antibody. The crystal structure was obtained from the Protein Data Bank (PDB entry 1IGT). The IgG antibody is composed of two heavy chains (red and green) and two light chains (orange and blue). The crystal structure was viewed and analyzed using PyMOL (The PyMOL Molecular Graphics System, Version 2.4.0 Schrödinger, LLC.).
Over the last two decades, our understanding of the molecular mechanisms underlying HNCs, and developments in molecular biology, have led to the development of different targeted therapeutic agents. HNCs can be generally prompted by a primary lesion or metastasize from another cancerous site leading to malignant tumor. Cancer stem cells are constantly addressed as one of the primary mediators of tumor aggressiveness, relapse, and malignancy (
Currently and to the best of our knowledge, there are 51 antibodies are being tested at preclinical or clinical trials against HNCs (
List of approved and underdevelopment antibodies against head and neck cancer (HNC).
Product name | Involved companies | Class | Target | Type | Development stage ( |
|
---|---|---|---|---|---|---|
1 | Cetuximab | MedImmune (AstraZeneca), Merck & Co Inc, Bristol-Myers Squibb AB | IgG1 | Epidermal growth factor receptor (EGFR) | Chimeric | In 2006, the FDA has approved cetuximab in 2006 and currently is being used for: |
2 | Pembrolizumab | Merck & Co Inc | IgG4 | Programmed cell death protein 1 (PD-1) | Humanized | The FDA approved pembrolizumab in 2019 as a first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma. |
3 | Nivolumab | Bristol-Myers Squibb (Medarex) and Ono Pharmaceutical | IgG4 | PD-1 | Human | The FDA approved nivolumab in 2016 for patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) following progression on platinum-based therapy. |
4 | Toripalimab | Shanghai Junshi Biosciences Co., Ltd | IgG4 | PD-1 | Humanized | NCT04126460 (phase II) NCT04164238 (phase II) NCT03952065 (phase III) NCT02915432 (phase I/II) |
5 | Bevacizumab | Genentech (Roche) | IgG1 | Vascular endothelial growth factor A (VEGF-A) | Humanized | NCT01588431 (phase II) NCT00588770 (phase III) NCT03818061 (phase II) |
6 | Atezolizumab | Genentech (Roche) | IgG1 | Programmed death-ligand 1 (PD-L1) | Humanized | NCT03708224 (phase II) NCT02423863 (phase II) NCT03818061 (phase II) NCT03829501 (phase I/II) NCT03452137 (phase III) NCT03289962 (phase I) NCT03212469 (phase I/II) NCT03170960 (phase I/II) NCT03313804 (phase II) NCT03841110 (phase I NCT03386721 (phase II) NCT03228667 (phase II) |
7 | Avelumab | Merck KGaA and Pfizer Inc | IgG1 | PD-L1 | Human | NCT03844763 (phase I/II) NCT03494322 (phase II) NCT04052204 (phase II) NCT03260023 (phase I/II) NCT02999087 (phase III) NCT03409458 (phase I/II) NCT03498378 (phase I) NCT02952586 (phase III/terminated due to lack of efficacy) |
8 | Tremelimumab | Pfizer and MedImmune (AstraZeneca) | IgG2 | Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) | Human | NCT03019003 (phase I/II) NCT02551159 (phase III) NCT02999087 (phase III) NCT02369874 (phase III) NCT03283605 (phase I/II) NCT02319044 (phase II) NCT03212469 (phase I/II) NCT03426657 (phase II) NCT03624231 (phase II) NCT03518606 (phase I/II) NCT03292250 (phase II) NCT03522584 (phase I/II) NCT02643303 (phase I/II) NCT03509012 (phase I) NCT03529422 (phase I) |
9 | Varlilumab | Celldex Therapeutics and Bristol-Myers Squibb AB | IgG1 | CD27 (TNFRSF7) | Human | NCT02543645 (phase I; terminated) NCT02335918 (phase I/II; completed) |
10 | Patritumab | Daiichi Sankyo Inc | IgG1 | Receptor tyrosine-protein kinase erbB-3 (HER3) | Human | NCT02350712 (phase I; completed) NCT02633800 (phase II; terminated) |
11 | Durvalumab | MedImmune (AstraZeneca) | IgG1 | PD-L1 | Human | NCT03019003 (phase I/II) NCT03162224 (phase I/II) NCT02291055 (phase I/II) NCT02997332 (phase I) NCT02551159 (phase III) NCT03829007 (phase I/II) NCT02369874 (phase III) NCT03737968 (phase II) NCT03051906 (phase I/II) NCT03258554 (phase II/III) NCT03691714 (phase II) NCT02207530 (phase II) NCT02319044 (phase II) NCT03292250 (phase II) NCT02318277 (phase I/II) NCT02423863 (phase II) NCT03518606 (phase I/II) NCT02499328 (phase I/II) NCT04262388 (phase II) NCT03983954 (phase I) NCT03212469 (phase I/II) NCT03739931 (phase I) |
12 | Tomuzotuximab | Glycotope GmbH, Octapharma AG | IgG1 | EGFR | Human | NCT02052960 (phase II) |
13 | Monalizumab | Innate Pharma SA and AstraZeneca | IgG4 | CD94/NK group 2 member A (NKG2A) | Humanized | NCT02643550 (phase I/II) |
14 | Utomilumab | MorphoSys AG, Pfizer Inc | IgG2 | CD137 (4-1BB) | Human | NCT02554812 (phase II) |
15 | Cixutumumab | ImClone Systems (Eli Lilly) | IgG1 | Insulin-like growth factor 1 (IGF-1) receptor | Human | NCT00617734 (phase II; completed) |
16 | Duligotuzumab | Genentech (Roche) | IgG1 | HER3 | Humanized | NCT01911598 (phase I; completed) |
17 | PF04518600 | Pfizer | IgG2 | OX40 protein (CD134) | Human | NCT02315066 (phase I) |
18 | IPH2102 (Lirilumab) | Innate Pharma SA and Bristol-Myers Squibb AB | IgG4 | KIR2DL1/2/3 | Human | EU clinical trial: CA223-001 (phase I/II) |
19 | Spartalizumab | Novartis | IgG4 | PD-1 | Humanized | NCT04213404 (phase I) NCT04000529 (phase I) |
20 | Sym004 (two mAbs, futuximab, and modotuximab) | Symphogen A/S | IgG1 | EGFR | Chimeric | NCT01417936 (phase II; completed) |
21 | Ficlatuzumab | AVEO Oncology | IgG1 | Human hepatocyte growth factor/scatter factor (HGF/SF) ligand | Humanized | NCT03422536 (phase II) |
22 | ARGX110 (Cusatuzumab) | Argenx SE and Janssen Research & Development, LLC | IgG1 | CD70 | Humanized-defucosylated | NCT02759250 (phase I; completed) |
23 | Urelumab | Bristol-Myers Squibb AB | IgG4 | CD137 (4-1BB ligand) | Human | NCT02110082 (phase I; completed) |
24 | Cemiplimab-rwlc | Regeneron and Sanofi | IgG4 | PD-1 | Human | NCT04242173 (phase II) |
25 | Dalantercept | Acceleron Pharma Inc | Fc of IgG1 | Activin receptor-like kinase 1 (ALK1) | ALK1-Fc fusion protein | NCT01458392 (phase II; completed) |
26 | FRMD4A antibody | Cancer Research Technology | Not specified | FERM domain containing 4A (FRMD4A) | Not specified | Preclinical |
27 | Zalutumumab | Genmab A/S | IgG1 | EGFR | Human | NCT00401401 (phase I/II; terminated) |
28 | Nimotuzumab | CIMYM BioScience and Oncoscience AG | IgG1 | EGFR | Humanized | NCT00957086 (phase III) |
29 | Daromun | Philogen SpA | ScFv | Extra-domain B (ED-B) of fibronectin (L19) and fibromun (L19-TNFalpha) | Fusion (A combination of darleukin (L19-IL2), fused to a human scFv | Preclinical |
30 | ABL001 | ABL Bio | IgG1-ScFv | VEGF/DLL4 (Delta Like Canonical Notch Ligand 4) | Bispecific antibody (humanized bevacizumab and a Dll4-targeting ScFv) | NCT03292783 (phase I) |
31 | Panitumumab | Abgenix Inc and Amgen | IgG2 | EGFR | Human | NCT02415881 (phase I) NCT03733210 (phase I) NCT03405142 (phase I) |
32 | Enoblituzumab | MacroGenics | IgG1 | CD276 (B7-H3) | Humanized | NCT04129320 (phase II/III) NCT02475213 (phase I) |
33 | Bavituximab | Peregrine Pharmaceuticals | IgG1 | Phosphatidylserine | Chimeric | NCT04150900 (phase I) |
34 | Telisotuzumab vedotin (ABBV-399) | AbbVie | IgG1 | Tyrosine-protein kinase Met (c-Met) | Humanized ADC (Ab-MMAE) | Preclinical |
35 | Budigalimab (ABBV-181) | AbbVie | IgG1 | PD-L1 | Humanized | NCT04196283 (phase I) NCT03000257 (phase I) |
36 | Cosibelimab | Checkpoint Therapeutics | IgG1 | PD-L1 | Human | NCT03212404 (phase I) |
37 | CPI-006 | Corvus Pharmaceuticals | IgG1 | CD73 (NT5E: ecto-5′-nucleotidase) | Humanized | NCT03454451 (phase I) |
38 | Hu5F9-G4 | Forty Seven, Inc. | IgG4 | CD47 | Humanized | NCT02953782 (phase I) |
39 | W0101 | Pierre Fabre | IgG1 | Insulin-like growth factor 1 receptor (IGF-1R) | Humanized ADC (Ab-auristatin) | NCT03316638 (phase I/II) |
40 | Indatuximab ravtansine (BT-062) | ImmunoGen | IgG4 | CD138 (syndecan-1) | Chimeric ADC (Ab-ravtansine) | Preclinical |
41 | Tislelizumab (BGB-A317) | BeiGene | IgG4 | PD-1 | Humanized | NCT03430843 (phase III) NCT03783442 (phase III) NCT03957590 (phase III) NCT03924986 (phase III) |
42 | GBR 1372 | Glenmark Pharmaceuticals | Not specified | EGFRxCD3 | Bispecific antibody | Preclinical |
43 | ISU104 | ISU ABXIS Co | Not specified | HER3 | Human | NCT03552406 (phase I) |
44 | GA201 (RG7160): | Roche | IgG1 | EGFR | Humanized | NCT00721266 (phase I; completed) |
45 | LJM716 | Novartis AG | IgG1 | HER3 | Human | NCT01598077 (phase I; completed) |
46 | Siltuximab | Centocor, Inc (Janssen Biotech). | IgG1 | IL6 | Chimeric | NCT00841191 (phase I/II) |
47 | Vopratelimab (JTX-2011) | Jounce Therapeutics, Inc. | IgG1 | ICOS | Humanized | NCT04319224 (phase I/II) NCT02904226 (phase I/II) |
48 | Ipilimumab | Bristol-Myers Squibb | IgG1 | CTLA-4 | Human | NCT02812524 (phase I) NCT02919683 (phase II) NCT02741570 (phase III) NCT02823574 (phase II) NCT04080804 (phase II) NCT03690986 (phase I) NCT03700905 (phase III) NCT03162731 (phase I) NCT01935921 (phase I) NCT03003637 (phase I/II) NCT03406247 (phase II) NCT03620123 (phase II) |
49 | Trastuzumab | Genentech (Roche) | IgG1 | HER2 | Humanized | NCT00004163 (phase II) NCT02627274 (phase I) |
50 | Pertuzumab | Genentech (Roche) | IgG1 | HER2 | Humanized | NCT02465060 (phase II) |
51 | Onartuzumab | Genentech (Roche) | IgG1 | c-Met | Humanized | Preclinical (Fab fragments with murine variable domains fused to human IgG1 constant domains) |
Each listed antibody was described in term of type, class, targeted antigen, involved companies, as well as details of the clinical development stage based on information available on
Each listed antibody was described in term of type, class, targeted antigen, involved companies, as well as details of the clinical development stage based on information available on ClinicalTrials.gov.
EGFR is a glycoprotein belonging to the ErbB receptor family, and it is composed of an extracellular ligand-binding domain, an intracellular tyrosine kinase domain, and a hydrophobic transmembrane segment (
EGFRs are expressed on the cell surface, and the mitogen-activated protein kinases (MAPK) pathway is the most important pathway in mediating the biological response of the EGFR (
Therapeutic antibodies were developed to target the extracellular domain of EGFR as demonstrated by cetuximab. This strategy was designed to avert receptor activation by endogenous ligands via competitive inhibition. In addition, it can internalize the antibody-receptor complex, and successively downregulate the EGFR expression (
Cetuximab biosimilars.
Product name | Development stage | Involved company | |
---|---|---|---|
1 | Cetuximab biosimilar ONS1055 | Preclinical | Oncobiologics and Outlook Therapeutics |
2 | Cetuximab biosimilar RPH002 | Phase III | R-Pharm |
3 | Cetuximab biosimilar ONS1055 | Preclinical | Viropro, Oncobiologics, and Outlook Therapeutics |
4 | Cetuximab biosimilar ABP494 | Preclinical | Actavis, Allergan, and Amgen |
5 | Cetuximab biosimilar HLX05 | Preclinical | Shanghai Henlius Biotech Inc |
6 | Cetuximab biosimilar ABP494 | Preclinical | Actavis, Allergan, and Amgen |
7 | Cetuximab platform | Research | PlantForm Corporation |
8 | Cetuximab biosimilar CT-P15 | Research | Celltrion |
9 | Cetuximab biosimilar BNV003 | Research | Bionovis SA |
10 | Cetuximab platform | Research | PharmaPraxis |
11 | Cetuximab biosimilar CMAB009 | Phase I/II/III | Mabtech, Shanghai Zhangjiang Biotechnology, and Sinomab |
12 | Cetuximab biosimilar KL 140 | Phase I/II/III | Sichuan Kelun Pharmaceutical Research Institute |
13 | Cetuximab biosimilar CDP-1 | Phase I/II/III | Dragonboat Biopharmaceutical |
14 | Cetuximab biosimilar (STI-001) | Phase III | Mabtech |
15 | Cetuximab biosimilar | Research | BioXpress Therapeutics |
Besides Cetuximab there are seven other antibody-based projects that are being developed against EGFR, including tomuzotuximab, Sym004, Zalutumumab, nimotuzumab, GA201 (RG7160), GBR 1372, and panitumumab (
Aligned structures of panitumumab and cetuximab. Crystal structures of panitumumab (red) and cetuximab (blue) were aligned while binding to EGFR (gray). Both crystallized antibodies were in Fab format. Crystal structures were viewed and analyzed using PyMOL (The PyMOL Molecular Graphics System, Version 2.4.0 Schrödinger, LLC.)
Circulating T lymphocytes normally examine the identity of other cells in the body to differentiate self from non-self antigens are therefore referred to as “checks.” This is achieved when a receptor binds to an equivalent ligand on a host cell, which will enable the T cells to identify it as a host cell, and prevents the triggering of an immune response (
PD-1 (CD279) is a type I transmembrane receptor with extracellular domains comparable with canonical immunoglobulin, and is responsible for signal transduction to intracellular domains (
The initial immunotherapeutic agents to reveal indication of response durability and survival advantage in platinum-pre-treated recurrent and metastatic HNC are anti-PD-1 monoclonal antibodies (
The outcomes of the KEYNOTE-048 study have confirmed the substantial effect of anti-PD-1 in the first line recurrent and metastatic HNC setting (
Crystal structures of anti PD-1 and PD-L1 antibodies. Crystal structures of
The other checkpoint target is CTLA-4 (CD152). As a B7/CD28 family member, CTLA-4 can inhibit T cell functions (
Human CTLA-4 includes a leader peptide and three domains: an extracellular V domain (116 amino acids), a transmembrane region (37 amino acids) and cytoplasmic tail (34 amino acid) that contains two tyrosine-based motifs (
Aligned structures of Tremelimumab and Ipilimumab. Crystal structures of Ipilimumab (red) and tremelimumab (blue) were aligned while binding to EGFR (gray). Both crystallized antibodies were in Fab format. Crystal structures were viewed and analyzed using PyMOL (The PyMOL Molecular Graphics System, Version 2.4.0 Schrödinger, LLC.)
Despite the great potential of biotherapeutic antibodies in treating various types of cancer, the scenario is slightly more complicated in HNCs. HNC is very costly to be treated, and in the USA for example, it is considered to be the most expensive cancer to treat, with assessed costs of $96,000–$150,000 for multimodality treatment (
Regarding the anti-EGFR antibodies, despite the 80–90% overexpression of EGFR in HNC, Cetuximab therapy is potent in only 10–20% of HNC patients (
HNCs can additionally develop resistance to cetuximab (
Another anti-EGFR is panitumumab, which was tested on patients with recurrent or metastatic HNC in the SPECTRUM trial (phase III) that examined cisplatin and fluorouracil with/without panitumumab (
EGFR is expressed at the epidermis basal layer, so it is anticipated that skin toxicity, such as acneiform eruptions, could be a major side effect (
On the other hand, immune checkpoint inhibitors (ICIs) show promising clinical benefit when generally compared to anti-EGFR antibodies. However, they can also cause a distinctive spectrum of side effects, influencing almost any organ. Shah et al. (
Analysis of other clinical trials, which involved various ICIs, indicated that merely ~15% of patients with refractory/metastatic HNC attained curable remissions and extended survival (
Nanotechnology has rapidly progressed to provide pronounced promise in combating cancer (
Effective cancer treatments should distinguish between malignant from non-malignant cells, and to specifically destroy malignant cells (
Nanoparticles-based approaches in head and neck cancer.
Nanoparticle (NP) type | Application | Responsible party | Development stage ( |
|
---|---|---|---|---|
1 | Silica NP and experimental dye-labeled particle (dots), cRGDY-PEG-Cy5.5-C dots | Imaging | Memorial Sloan Kettering Cancer Center | NCT02106598 (phase I/II, recruiting) |
2 | Albumin stabilized NP and paclitaxel | Treatment | University of Southern California | NCT02495896 (phase I, active, not recruiting) |
3 | Albumin stabilized NP and paclitaxel | Treatment | Washington University School of Medicine | NCT01566435 (phase II, active, not recruiting) |
4 | Ferumoxytol (iron oxide) NP | Imaging | M.D. Anderson Cancer Center | NCT01895829 (phase I, active, not recruiting) |
5 | Silicon incorporated with quaternary ammonium polyethylenimine (PEI) NP | Device | Hadassah Medical Organization | NCT01007240 (phase I, unknown) |
6 | Hafnium oxide (HfO2) nanoparticle | Treatment | Nanobiotix | NCT01946867 (phase I, unknown) |
7 | Lipid NP encapsulating three mRNAs encoding human OX40L, interleukin 23 (IL23), and interleukin 36γ (IL36γ) | Treatment | Moderna Therapeutics | NCT03739931 (phase I, unknown) |
Nanoparticles could be adapted as dendrimers, liposomes, polymers, iron oxide, nanotubes, nanowires, and gold nanoparticles (GNPs) (
The concept of photothermal therapy is based on the application of a laser light at a specific wavelength to the surface of GNPs, which can trigger the surface electrons to be excited and resonate strongly, and conversion of light into heat swiftly happens (
GNPs have been investigated in different sizes and morphologies, for example nanorods (GNRs), nanospheres (GNSs), nanostars, hollow nanoshells, nanorings, and nanocages (
Both GNSs and GNRs were used to generate photothermal effect within the visible or NIR region, respectively. El-Sayed et al., have initially used anti-EGFR antibody conjugated to GNSs (
Despite the aforementioned advantages of GNPs, there is a possible long-term toxicity owing to sluggish tissue clearance, which is a factor that requires attention before GNPs can be used
Another major limitation is related to cetyltrimethyl ammonium bromide (CTAB) that is broadly implemented in the synthesis of GNRs in seed-mediated growth (
The conjugation of GNRs to antibodies represents a great advantage, since it will combine the high specificity of the antibody with the enormous optical potential of GNPs. However, the antibody target that can be used in this targeting process is of crucial importance. In addition, these antibodies should be carefully conjugated to GNRs to avoid loss of targeting efficacy due to steric hindrance. The conjugation process should be directed to a specific region within the antibody using a suitable linker, without affecting the specific binding regions for target detection. Therefore the size, shape, and surface modification of the implemented GNRs are key factors that will complement the overall success of these therapies.
HNC represents an immense clinical problem that requires special attention. The HNC treatment approaches are based on surgery, RT, CT, and biotherapeutic antibodies. Both RT and CT are well known for their severe side effects, and surgery can result in serious facial disfiguration and loose of ability to smell, speak, or taste. Antibodies have shown remarkable success in treating various types of cancer. Nevertheless, the complexity of HNC has relatively hindered this success. The three licensed antibodies against HNC are only being used in combination with other treatment modalities. Numerous monoclonal antibodies, ADCs, and bispecific antibodies are under development. The efficacy of these antibodies could be enhanced through conjugation to GNPs, and the generation of photothermal therapies. These photothermal therapies can specifically destroy cancer cells and treat HNC in an effective way. In order to gain a maximum photothermal effect the main three components (GNPs, linker, and the antibody) require careful optimizations.
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The author is employed by the company SiMologics Ltd.