Developing Biotherapeutics for Lung Cancer Treatment

In recent years, biologics — drugs derived from living culture systems — have become increasingly significant in the fight against a plethora of conditions, such as inflammatory diseases, autoimmune disorders, and cancers. Unfortunately, the efficiency of these drugs comes at a cost. A daily dose of a biologic drug costs, on average, 22 times more than conventional small-molecule drugs (Makurvet 2021). Therefore, the development of biosimilars is hoped to reduce the costs of these drugs, making them more accessible to those in need of treatment. Lung cancer is an example where the development of biosimilars could increase treatment options available for patients.

The increased cost of biologics compared to small-molecule drugs is partly due to the complexity of their development and manufacture. Additionally, the small-molecule drug market has significantly more competitors producing generic drug versions, driving down customer costs (Makurvet 2021). A critical component in the strategy to reduce rising drug costs is the development of biosimilars, which, as their name suggests, are highly similar iterations of brand-name biologics. The production of biosimilars has been estimated to save the U.S. healthcare system approximately $38.4 billion between 2021 and 2025 (Mulcahy et al. 2022).

The development of biosimilars requires extensive preclinical and clinical data, including pharmacokinetics (PK) and immunogenicity assessments (Ventola 2013). Bio-Rad offers a range of anti-idiotypic antibodies against various antibody drugs to allow the evaluation of new biosimilars via the development of highly selective and sensitive PK and anti-drug antibody (ADA) assays. In this extensive range, there are many anti-idiotypic antibodies against drugs targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) immune checkpoint pathways, used in the treatment of cancers, including lung cancer (Table 1).

Table 1. Bio-Rad’s range of anti-idiotypic antibodies against PD-1/PD-L1 and CTLA-4 inhibitors.

* Affinity measured in the monovalent Fab format.
¹ Monovalent Fab antibody with DYKDDDDK (F), SpyTag version 2 (Spy2), and His-6-tags (H).
² Monovalent Fab antibody with DYKDDDDK (F) and StrepX-StrepX (Sx2) tags.
³ Monovalent Fab antibody DYKDDDDK- and His-6-tags.

Immune Checkpoint Inhibitors in Lung Cancer

In the U.S., lung cancer has become one of the leading causes of cancer-related deaths, with approximately 225,000 newly diagnosed patients and 160,000 deaths each year (Siddiqui et al. 2023). Broadly, lung cancer can be divided into two categories: (1) small cell lung cancer (SCLC), which makes up around 15% of lung cancers and is typically more aggressive with a poorer prognosis, and (2) non–small cell lung cancer (NSCLC), comprising the remaining 85% (Rudin et al. 2021).

Immune checkpoint inhibitors are a class of drugs that have been approved for the treatment of a variety of cancers due to their ability to reinvigorate the immune system, which is often suppressed by cancers to facilitate their continuous growth. Under normal conditions, immune responses are restrained by these checkpoint pathways to mitigate potential damage from excessive inflammation.

Cancer cells have cunningly evolved the ability to hijack these checkpoint mechanisms to evade elimination by the immune response, making immune checkpoint pathways an attractive target for cancer therapy (Pardoll 2012). Several immune checkpoint inhibitors have proven to be efficacious in NSCLC treatment and have since been approved for clinical use, namely cemiplimab, nivolumab, atezolizumab, pembrolizumab, durvalumab, and ipilimumab. While fewer have been approved for SCLC therapy, many are currently under investigation (Basumallik and Agarwal 2023). These monoclonal antibodies target the PD-1/PD-L1 pathway or the CTLA-4 pathway.

The PD-1/PD-L1 Pathway

PD-1 is a transmembrane receptor normally expressed on T cells upon activation, as well as on natural killer (NK) cells, B cells, dendritic cells (DCs), macrophages, and monocytes. In particular, tumor-infiltrating CD8⁺ T cells have been shown to express remarkably high levels of this receptor (Ahmadzadeh et al. 2009).

PD-L1, PD-1’s corresponding ligand, is generally expressed under inflammatory conditions on macrophages, DCs, some activated T and B cells, and some epithelial cells. However, PD-L1 expression has also been appropriated by cancer cells within tumors for escaping anti-tumor responses.

Upon PD-L1 (on tumor cells) binding to PD-1 (on T cells), a signaling cascade is initiated, resulting in an “off” signal to T cells via the inhibition of T-cell receptor (TCR)–mediated activation, proliferation, and cytokine production, as well as inducing their apoptosis. These events impede the ability of the immune system to destroy the cancer cells, thus allowing for cell division and tumor growth (Han et al. 2020).

Monoclonal antibodies have been developed to specifically disrupt this pathway, either via the blockade of PD-1 — as is the case for cemiplimab, nivolumab, and pembrolizumab — or through the blockade of PD-L1, as is for durvalumab and atezolizumab. These drugs have since been approved for the treatment of patients with lung cancer.

The Success of Blocking PD-1/PD-L1 in Lung Cancer Treatment

In 2022, the market of PD-1/PD-L1 inhibitors was valued at $30.54 billion. Various clinical trials have confirmed the efficacy of these drugs in patients. For example, patients with advanced squamous cell NSCLC revealed (at one year of treatment) an overall survival (OS) rate of 42% with nivolumab, compared to 24% with the well-established anti-mitotic chemotherapeutic drug docetaxel; likewise, in nonsquamous NSCLC, the OS rate of nivolumab to docetaxel was 51% versus 39% (Brahmer et al. 2015, Borghaei et al. 2015). Additionally, the OS in treated NSCLC patients was 12.6 months with atezolizumab, 12.7 months with pembrolizumab, and, notably, 9.7 months with docetaxel (Fehrenbacher et al. 2016, Herbst et al. 2016). Lastly, cemiplimab-treatment exhibited a median OS of 26.1 months compared to 13.3 months with chemotherapy (Özgüroğlu et al. 2023).

Furthermore, durvalumab was approved by the FDA in 2018 for the treatment of unresectable stage three NSCLC in patients who did not respond to chemoradiotherapy; at 18 months, the progression-free survival (PFS) rate was 44.2% in durvalumab-treated individuals compared to 27% in the placebo group (Antonia et al. 2017). Remarkably, durvalumab was approved shortly after for the treatment of extensive-stage SCLC (ES-SCLC) in combination with other standard chemotherapies (Paz-Ares et al. 2019).

Although blockade of the PD-1/PD-L1 pathway has provided effective treatment options for numerous patients, many still do not respond, particularly those with low or absent PD-L1 expression in tumors. Fortunately, other immune checkpoint inhibitors that act on different pathways offer alternatives.

Targeting the CTLA-4 Pathway

For T cells to become activated, they must be stimulated by their cognate antigen, presented by the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APCs), and receive co-stimulatory signals to induce their proliferation and survival. One such co-stimulation pathway is the binding of CD80 or CD86 (on the surface of APCs) to their receptor, CD28 (expressed on the surface of T cells). The absence of CD28 stimulation upon TCR binding leads to anergy or apoptosis of the T cell.

CTLA-4 (also known as CD152) is a transmembrane receptor with high structural similarity to CD28 (from the same immunoglobulin gene superfamily) and also binds to CD80 and CD86. However, CTLA-4 binding to these ligands does not produce a stimulatory signal and thus acts as a negative regulator of T-cell immunity by competing with CD28 (Buchbinder and Desai 2016). CTLA-4 is expressed on T cells upon their activation to limit an excessive response. Interestingly, many tumor cells have been shown to constitutively express CTLA-4, allowing tumor cells to dampen the T-cell response that would otherwise work towards their elimination (Contardi et al. 2005).

Ipilimumab is a monoclonal antibody that binds and blocks CTLA-4 engagement with its ligands and is approved in combination with nivolumab for the treatment of NSCLC. In a phase III clinical trial, patients with stage four or recurrent NSCLC treated with the combination of nivolumab and ipilimumab had a significantly higher one-year PFS than those treated with chemotherapy — 42.6% versus 13.2% (Hellmann et al. 2018).

Summary

Overall, targeting immune checkpoint pathways in biotherapeutic development for lung cancer treatment remains an enticing option, particularly with the introduction of biosimilars. Biosimilars are driving down prices for treatment and improving access to effective therapies.

The development of biosimilars requires the ability to determine the pharmacokinetics of the drug, as well as to examine any immune response mounted against the drug. At Bio-Rad, we develop highly specific, high-affinity, anti-idiotypic antibodies that allow the assessment of biosimilars in preclinical research, clinical development, and patient response monitoring. In addition to quantifying free-drug levels with anti-idiotypic antibodies, Bio-Rad offers drug-target complex binders (type 3 antibodies) used to evaluate levels of bound drug. Bio-Rad offers a wide range of ready-made antibodies against on-market biotherapeutic drugs and provides a custom antibody generation service. The custom service enables the design of antibodies specific to your biotherapeutic target using HuCAL® technology — facilitating and accelerating your drug development process.

To start or continue your Bio-Rad biologics journey, visit our anti-idiotypic antibody page for more information.

References

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