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Castrignano, C.; Di Scipio, F.; Franco, F.; Mognetti, B.; Berta, G.N. Nanobodies for HER2+ Breast Cancer. Encyclopedia. Available online: (accessed on 14 June 2024).
Castrignano C, Di Scipio F, Franco F, Mognetti B, Berta GN. Nanobodies for HER2+ Breast Cancer. Encyclopedia. Available at: Accessed June 14, 2024.
Castrignano, Chiara, Federica Di Scipio, Francesco Franco, Barbara Mognetti, Giovanni Nicolao Berta. "Nanobodies for HER2+ Breast Cancer" Encyclopedia, (accessed June 14, 2024).
Castrignano, C., Di Scipio, F., Franco, F., Mognetti, B., & Berta, G.N. (2023, May 31). Nanobodies for HER2+ Breast Cancer. In Encyclopedia.
Castrignano, Chiara, et al. "Nanobodies for HER2+ Breast Cancer." Encyclopedia. Web. 31 May, 2023.
Nanobodies for HER2+ Breast Cancer

The serendipitous discovery of nanobodies (NBs) opened the door to new possibilities for innovative strategies, particularly in cancer treatment. These antigen-binding fragments are derived from heavy-chain-only antibodies naturally found in the serum of camelids and sharks. NBs are an appealing agent for the progress of innovative therapeutic strategies because they combine the advantageous assets of smaller molecules and conventional monoclonal antibodies (mAbs). 

nanobody target therapy HER2 breast cancer

1. Introduction

Target therapy is a breakthrough strategy slowly paving the way for precision medicine [1]. Essentially, it involves therapeutic methods to target specific pathogenic proteins, cells, or genes within a broader context by exploiting the drug’s ability to bind only the disease-causing molecules while not affecting healthy tissues [2]. Among the medications employed in target treatment, two categories have been principally developed: tyrosine-kinase inhibitors and monoclonal antibodies (mAbs), which are mostly used nowadays [3].

2. NBs for the Diagnosis of HER2

2.1. Radioisotope-Based Diagnostic Techniques

Due to its non-invasive nature and ability to offer significant clinical evidence on tumors, molecular imaging (MI) is widely employed in the detection of malignancies [4]. A specific moiety that is to be labeled with a diagnostic radioisotope or an appropriate fluorophore is the principle of this approach [5]. NBs are excellent candidates for MI applications thanks to the above-mentioned properties and their viability and safety have been validated for human use [6][7][8]. In non-targeted organs, with the exception of the kidneys, radiolabeled NBs are typically poorly absorbed, which triggers a high target-to-background ratio soon after administration. As a result, same-day imaging is possible and shorter-lived radioisotopes can be used, which is an improvement over the low target-to-background ratio that is observed quickly after the injection of a full-sized mAb for the same purpose [9]. These properties give rise to NBs’ application in MI methods such as Positron Emission Tomography (PET), Single-Photon Emission Computed Tomography (SPECT), Near Infra-Red (NIR), and Ultrasound-Based Molecular Imaging [10].
Several anti-HER2 NBs have already been employed: along with 18F, 68Ga was one of the first positron-emitting isotopes to be used for PET NB labeling, since they both had comparably short half-lives (109.8 min and 68 min, respectively), making them especially well-suited for MI [4]. Radioisotope accumulation in tumors is increased by NB labeling, allowing for non-invasive detection techniques sensitive down to a picomolar level [11].
Among the pre-clinical trials, in vivo PET/CT imaging of HER2+ tumor-bearing mice was carried out to demonstrate the suitable radiolabeling qualities for 18F [12]. The outcomes were comparable if not even better than those reported with 68Ga-conjugated NBs, most likely because of the radioisotope having a slightly longer half-life. Similarly, the use of 131I-NBs has demonstrated high specificity and affinity for the targeted antigens, resulting in excellent imaging contrast and sensitivity as assessed by PET. By generating a 131I-HER2-NB-conjugated radionuclide, Feng et al. [13] proved that, while both site-specific and random NB-tracer conjugation had comparable tumor targeting abilities, the former resulted in lesser accumulation in normal tissues in breast cancer xenograft mice. Ultimately, in a phase I trial on 68Ga-HER2-NB, Keyaerts et al. [6] validated the rapid blood clearance with just 10% of the injected activity still in circulation 1 h post-injection. The conjugate was evaluated on 20 women diagnosed with HER2+ breast cancer, either primary or metastatic. Although there was a significant absorption in the kidneys and liver, all other organs that frequently host primary breast cancer or metastases had very low background levels, resulting in an overall favorable 68Ga-HER2-NB biodistribution with minimal to no side effects observed. Because this tumor-targeting strategy revealed promising potential, the evaluation of this tracer advanced to the phase II stage for the assessment of brain metastases detection in breast cancer patients [7].
SPECT, on the other hand, uses γ-emitting radioisotopes; in a pre-clinical study, the 99mTc radioisotope was first used to assess tumor accumulation in mice with breast cancer xenografts [14]. The NB-conjugated tracer accumulated visibly at the tumor site of HER2+ xenograft-bearing mice, yet no tumor localization was detected in HER2-xenografted mouse tumors. Only recently, Zhao et al. [15] developed a 99mTc-labeled anti-HER2 NB to investigate its potential as a brand-new tracer for SPECT/CT evaluation of HER2 expression in breast cancer patients. Ten women with both primary and metastatic cancer participated in an open, non-randomized, first-in-human phase I clinical trial. Again, livers and kidneys were the primary sites of uptake but a very low level of radioactivity persisted in the blood and lungs for the first hour following the injection, which allowed for a better tumor-to-background signal within the following hour. Due to the high activity in the circulatory system, the rapid blood clearance not only enabled the conduction of SPECT imaging at early time points but also helped to lower the likelihood of false-positive results. Furthermore, it was possible to achieve significantly greater signal-to-noise ratios for images taken two hours post-injection due to a rapid tracer reduction in the healthy lung tissue, which increased the contrast of the primary and metastatic cancers in the images. In addition, unlike Ab-derived radiotracers, the 99mTc-HER2-NB tracer is designed not to target the same HER2 epitope as the therapeutic Abs, thus avoiding the effect that the circulating drug might have on tumor uptake. The effectiveness of this NB-radioisotope conjugate will most likely be examined in future studies with larger cohorts.

2.2. Non-Radioisotope-Based Diagnostic Techniques

Nonetheless, the risk of radiation exposure for both the patient and the clinician remains a clear drawback of the use of radioisotopes as imaging agents. In theory, isotopes with a short half-life and high positron emission, namely 18F, could allow imaging promptly after administration. However, this implies that key parameters such as blood clearance and tissue penetration are compatible with the visibility of the interested target [16]. As a consequence, non-radioisotope-based techniques tend to be interesting options, even though they too have drawbacks. Albeit, tissue and body fluids can absorb excitation light and emission wavelengths, fluorescence-based approaches might as well be a viable option. Using appropriately labeled NBs is the only way to perform these specific optic techniques. In their study for the assessment of the anti-HER2 NB drug conjugate, Xenaki et al. [17] performed an experiment on breast cancer-bearing mice xenografts that proved that these alternative strategies can be informative. The signal from HER2+ xenograft mice tumors could be revealed directly by coupling the anti-HER2 NB with a NIR (near-infrared) fluorophore, while still preserving adequate biodistribution. The perspective of a NIR-conjugated anti-HER2 NB could enable the precise non-invasive categorization of HER2+ cancers and more accurate surgical tumor removal in a future therapeutic context [18].

3. NBs against HER2 in Therapy

NBs targeting tumor-related receptors (EGFR family, VEGF, c-Met, etc.) are of particular relevance for therapeutic purposes. HER2 is among the most extensively researched oncogenes. Due to its overexpression in many cancers and its limited presence in healthy tissues, HER2 serves as both an oncogene and a good tumor antigen [14]. A single NB directed against HER2 is able to restrain cell mitosis and accelerate cell apoptosis, through the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. After treatment with an anti-HER2 NB, Western blot analysis of HER2+ breast cell lines (BT474 and SKBR3) revealed that the levels of p-AKT and p-ERK significantly dropped, whereas no fluctuations were observed in cell lines that weakly expressed the receptor (MCF-7) [19].

3.1. Identification of NBs against HER2 Extracellular Domain and Tyrosine-Kinase Domain

Approximately a decade ago, the first anti-HER2 NB (SR-87) was successfully isolated using phage display technology. This nanobody exhibited a high affinity for the extracellular domain of the target [20]. The subsequent strategy aimed to explore supplementary prospective domains that could be targeted in order to obstruct any possible divergent pathways that may still be functional or that could trigger a resistance reaction. Since then, a significant amount of research has focused not only on directing HER2 extracellular domain but also on NB binding alternative domains that play a role in the activation of the downstream pathways.
Ten years after the characterization of the extracellular domain-specific NB, Lamtha et al. [21] first managed to isolate a NB specifically directed against the HER2 tyrosine-kinase (TK) domain (VHH17); it had the potential to be further developed into a specific NB that binds and prevents the phosphorylation, therefore, provoking cell death. Starting from a humanized VHH phage library obtained from the venous blood collected from a naïve dromedary, the Ab selection was made using the HER2-TK recombinant protein as the antigen. VHH17 established a binding specifically with the HER2-TK activation loop (CDR1, CD2, and CDR3). The authors successfully managed to show the potential of employing a humanized NB phage display library to create a NB that binds specifically to the ATP-binding pocket and prevents the HER2-TK phosphorylation event. Therefore, this highlights the NB potential for decreasing the cancer cell viability, making it an attractive alternative as a HER2+ therapeutic agent.
However, there have been fewer reports concerning HER2 NBs that exert a suppressive role on HER2+ breast cancer. Whether this interesting approach is effective as an anti-cancer treatment will only be revealed by further studies.

3.2. Engineered NBs

3.2.1. Bispecific NBs against HER2

The prospect of designing HER2-targeting therapy for human tumors will be greatly simplified by manufacturing tumor-targeting HER2 NBs. Since 2013, many researchers have attempted to isolate anti-HER2 NBs from immunized Camelidae to first evaluate their efficacy in vitro [22]. The accessibility of these VHH libraries represents a promising prospect for establishing customized protocols that could potentially augment therapeutic efficacy and improve clinical outcomes. Wu et al. [23] originally showed that, similar to what is observed with Trastuzumab, when HER2+ or HER2− cells are treated with their anti-HER2 NB C3 coupled with a human IgG Fc alone (C3-Fc), no tumor cell growth inhibition was seen. On the other hand, when in the presence of NK cells, C3-Fc elicits potent Ab-dependent cell cytotoxicity against HER2+ cells both in vitro and in vivo, even stronger than that attributable to Trastuzumab. According to the epitope mapping investigation, C3-Fc interacts with HER2 extracellular domain through a different epitope than Trastuzumab [24]. This opens up the possibility of employing C3-Fc alone or in combination with another anti-HER2 Ab, delivering an additive or synergistic benefit to the therapy. This kind of construct is known as a “bispecific antibody”, and it is one of the methods being explored to address Ab resistance [25]. By possessing two distinct antigen binding sites, wherein one recognizes the tumor cells and the other the immune cells (typically T cells or NK cells), they can focus the immune system attention on the tumor cells themselves.
Several anti-HER2 bispecific Ab designs have been examined in the past [26][27][28][29]; however, they come with a number of shortcomings, such as a mixed population after purification, a low yield of production, a predisposition to aggregation, and a brief half-life. Research has recently focused on the potential to create a bispecific Ab that joins a Fab domain against CD3 to a VHH against HER2 or even a Fab domain against HER2 to a VHH against CD16 [28][30]. In this instance, these bispecific Abs can also effectively be secreted and purified in huge amounts from bacterial culture media, reducing the time and manufacturing costs. Once purified, they can exert lethal effects equivalent to, if not greater, than those of the therapeutic mAb alone on tumor cells that specifically overexpress HER2 both in vitro and in vivo, redirecting the T cells or NK cells effects only. With various formats of bispecific Abs targeting HER2+ cancer cells being tested, it will be interesting to observe how they each operate in patient care.

3.2.2. NBs as Drug Carriers

Most often the NB functions as a carrier that is conjugated to a targeting moiety rather than being the drug itself. NB modifications that are intended for conjugation can be carried out without endangering its targeting abilities: this enables the achievement of an effective loading capacity without the need to provide high dosages of the medication [31]. This suggests that, based on the weight of conjugates, NB delivers a considerably higher drug amount with the same drug-antibody ratio value than an Ab-drug conjugate [4]. Drug-loading capacity is defined by the amount of drug loaded per unit weight of vectors, and an NB has a far lower molecular weight than an Ab. Although a high drug-antibody ratio can be used to increase the efficacy of the Ab-drug conjugate itself, it might also decrease the mAb stability and promote drug clearance. Up to date, Trastuzumab emtansine [32] (approved by the FDA in 2013) and Trastuzumab deruxtecan [33] (approved by the FDA in 2022) are the only two clinically authorized humanized anti-HER2 mAbs currently used for treating HER2+ solid tumors. The main drawback of these conjugates, due to the characteristics of the Ab itself, is their heterogeneity in intra-tumoral distribution resulting in sluggish or confined tumor penetration (because of the previously described “binding-site barrier” phenomenon [34]).

3.2.3. Improving Pharmacokinetic Properties

When NBs are intended to be employed as cytotoxic drug carriers, the main drawback is their fast renal clearance, which results in a limited half-life in circulation [35]. Big efforts have been conducted so far to improve their unfavorable pharmacokinetic characteristics. The prospective employment of albumin or albumin domain-binding fusion, as well as PEGylation to increase the size above the glomerular filtration threshold, are all strategies that could extend the in vivo half-life of small therapeutics [36].
Xenaki et al. [17] tested the anti-HER2 NB 11A4 coupled with the albumin-binding domain as a possible targeting moiety for NB-drug conjugates’ development. As a result of their investigation, they demonstrated that NBs could serve as a platform for the generation of drug conjugates, providing a more comprehensive effect on tumor targeting. Since lengthening blood half-life is necessary for their in vivo effectiveness, coupling the anti-HER2 NB with an albumin-binding domain can successfully induce protracted and uniform accumulation in the tumor. According to their research, a single dose of an anti-HER2 Auristatin F drug exhibited remarkable efficacy in a pre-clinical model of HER2+ cells. Such long-circulating formulations have been demonstrated to preferentially collect within cancer as a result of the leaky vasculature created by tumors to maintain their growth.
To increase the therapeutic efficacy in HER2+ cancer cells, Farasat et al. [37] showed that a combination of four anti-HER2 NBs targeting various HER2 epitopes could be coupled on doxorubicin-loaded PEGylated liposomes. Because of the intrinsic specificity of NBs, the nano-complexes in this scenario were able to bind to HER2-overexpressing tumor cells, leading to a higher toxicity rate and fewer side effects. Similarly, polymeric nanoparticles gained popularity as nanocarriers over the past two decades thanks to their capacity to increase the physicochemical stability of their payload along with fairly good control over their release.
Along the lines of differently loaded PEGylated liposomes, Martínez-Jothar et al. [38] employed the same PEGylation approach to create a nanoparticle capable of encapsulating and delivering saporin, a novel anti-neoplastic agent inducing DNA breaks and apoptosis. By equipping the nanoparticle outer layer with NBs able to bind to cell surface receptors that are overexpressed in tumors, efficiency and selectivity were guaranteed. An 11A4 NB directed against HER2 was used to improve the polymeric NPs’ selective uptake by HER2+ breast cancer cells (SKBR3) in comparison to the HER2-cells (MDA-MB-231). After nanoparticle endocytosis occurred, the photochemical internalization approach was employed to trigger ROS production upon excitation with light of the proper wavelength; in this way, the endosomal membrane gets damaged and allows the release of the contained saporin into the cytosol. The selective NB-mediated endocytosis combined with the photochemical internalization enables the spatiotemporally and regulated release of the nanoparticles and their cargo from the endosome, consequently exposing the cells to saporin-damaging effects. A parallel approach may be employed to load therapeutic compounds into extracellular vesicles that overexpress anti-HER2 NBs on their surface [39]. This emerging drug delivery system is a natural means of eukaryotic intercellular communication, meaning that the ability to bypass cellular membranes can be exploited in non-immunogenic therapies.
This effectively demonstrates the versatility of an NB-based approach, prompting further testing in various types of cancer models as well NB-drug conjugates benefitting from enhanced drug solubility, circulation, decreased immunogenicity, and controlled release simply by undergoing a conjugation with a carrier molecule such as albumin or PEGylated particles.

3.2.4. NBs in Radiopharmaceutical Therapy

Current and proposed cancer treatment approaches in radiopharmaceutical therapy (RPT) include targeted radionuclide therapy, where the energy absorbed from radiation released by radionuclides with short path lengths (α- or β-particles, and Auger electrons) produces a biological effect [40]. By combining with high-specificity carriers (i.e., Abs [41]) or through physiological uptake, therapeutic radionuclides can build up in lesions of interest. RPT has emerged as an appealing cancer therapy option, particularly for individuals with metastatic disease, including breast carcinomas with HER2 overexpression [42]. For RPT to work, a radioactive atom and a tumor-targeting vector must be properly combined and the two must be linked in the right way. With fewer adverse effects than might be experienced with conventional radiotherapy, this ensures the possibility of increasing patient survival. It is, therefore, worth mentioning the prospective employment of NBs in RPT that has been evaluated during the last few years [43]. Feng et al. [44] conjugated the VHH_1028 anti-HER2 NB with a 131I-labeled prosthetic agent and its tissue distribution was analyzed in a murine HER2+ breast cancer xenograft model. The comparison was performed with another HER2-targeted radiopharmaceutical being tested in clinical trials ([131I]SGMIB-2Rs15d); 2Rs15d was the first anti-HER2 NB used as a targeted radionuclide agent for the treatment of HER2+ breast cancer, with tumor targeting, biodistribution, and safety evaluated in a pre-clinical investigation before moving on to a phase I clinical trial [45].
The results showed that iso-[131I]SGMIB-VHH_1028 exhibited 6.3 times more beneficial tumor-to-kidney radiation dosage ratios. Multiple-dose therapy regimens revealed that the compound was well tolerated, significantly slowed tumor development, and extended survival.
After successfully developing the 99mTc-NM-02 MI tracer with NM-02 NB as the lead compound [15], Zhao et al. recently investigated whether labeling said NB with 131I may be employed as a targeted radionuclide treatment agent for HER2+ breast cancer in xenografted mice [46].
Targeted α-particle therapy has also emerged as an appealing approach in RPT since it is able to exert cytotoxic effects via processes distinct from those used by already approved HER2-targeted pharmaceuticals. The use of α-particles makes it possible to irradiate metastases while causing the least possible damage to the nearby healthy tissues. HER2-targeted Abs were labeled with a range of α-emitters and their therapeutic potential was assessed in both animal models and patients [47]. Nevertheless, issues arose with the administration of such Abs, which was delayed and uneven. To overcome these obstacles, Feng et al. [48] substituted Abs with NBs as alternate scaffolding for targeted anticancer therapy, with a focus on the HER2-targeting moiety. In a prior work, they found that combining the prosthetic agent 211At labeling and the anti-HER2 NB properties might lead to an improved tumor targeting [49]. With this most recent study [48], they also verified the therapeutic efficacy of 211At-labeled NB conjugates, along with a long-lasting dosage-dependent effect following a single dose administration in a xenograft model for subcutaneous HER2+ breast cancer. Although further research into this targeted α-particles technique for the treatment of patients with HER2+ malignancies is required, the fast and even tumor penetration properties of NBs have once more come to light as desirable traits for yet another cancer target treatment.
Considering the preclinical results produced thus far, the utility of these NB tracers as theranostic agents has been widely recognized.


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