Molecular Farming of Pembrolizumab and Nivolumab

Abstract

Immune checkpoint inhibitors (ICIs) are a class of immunotherapy agents capable of alleviating the immunosuppressive effects exerted by tumorigenic cells. The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is one of the most ubiquitous checkpoints utilized by tumorigenic cells for immune evasion by inducing apoptosis and inhibiting the proliferation and cytokine production of T lymphocytes. Currently, the most frequently used ICIs targeting the PD-1/PD-L1 checkpoint include monoclonal antibodies (mAbs) pembrolizumab and nivolumab that bind to PD-1 on T lymphocytes and inhibit interaction with PD-L1 on tumorigenic cells. However, pembrolizumab and nivolumab are costly, and thus their accessibility is limited in low- and middle-income countries (LMICs). Therefore, it is essential to develop novel biomanufacturing platforms capable of reducing the cost of these two therapies. Molecular farming is one such platform utilizing plants for mAb production, and it has been demonstrated to be a rapid, low-cost, and scalable platform that can be potentially implemented in LMICs to diminish the exorbitant prices, ultimately leading to a significant reduction in cancer-related mortalities within these countries.

Keywords: cancer; immune checkpoint inhibitors; molecular farming; nivolumab; pembrolizumab.

Figure 1

Schematic representation of the PD-1/PD-L1 checkpoint and anti-PD-1 mAbs. The identification of tumorigenic cells by T lymphocytes depends on the recognition of tumor-associated antigens displayed on the major histocompatibility complex (MHC) class I protein through the binding of the T-cell receptor (TCR) [11]. Upon TCR activation, the T lymphocyte will initiate T-cell mediated cytotoxicity, ultimately leading to the induction of apoptosis in the tumorigenic cell [11]. However, tumorigenic cells upregulate the expression of PD-L1, which binds to its receptor PD-1 on T lymphocytes, consequently inhibiting TCR signaling and thus T-cell mediated cytotoxicity [35]. Anti-PD-1 mAbs inhibit the interaction of PD-1 to PD-L1, allowing TCR activation and signaling [36]. Image designed by MC Stark using Microsoft^® Office PowerPoint (Microsoft Office enterprise 2007, 2006 Microsoft Corporation, Redmond, WA, USA).

Figure 2

PD-1 cell signaling pathway. The binding of PD-L1 to PD-1 results in the phosphorylation of ITIM and ITSM, subsequently leading to the recruitment of SHP2, which goes on to inhibit the PI3K/Akt and RAS/MEK/ERK signaling pathways. Altogether, this leads to the inhibition of proliferation and cytokine production and the induction of apoptosis [35,40]. In addition, SHP2 stimulates phosphatase and tensin homolog (PTEN), which dephosphorylates PI3K—inhibiting its activity [45]. Image designed by MC Stark using Microsoft^® Office PowerPoint (Microsoft Office enterprise 2007, 2006 Microsoft Corporation, Redmond, WA, USA).