Pembrolizumab

A recombinant, single-chain, anti-CD19/anti-CD3 bispecific monoclonal antibody with potential immunostimulating and antineoplastic activities.

Pembrolizumab is a humanized monoclonal IgG4 kappa antibody directed against human cell surface PD-1 (programmed death receptor-1) on lymphocytes. The PD-1 receptor provides a critical “immune checkpoint,” which helps prevent the immune system from attacking itself. Certain tumors have a high expression of PD-L1(programmed death receptor ligand-1). Other tumor types use adaptive immune resistance, which takes the natural physiology of PD-L1 induction (protection of immune-mediated damage from infections) and adapts it to anti-tumor responses. When PD-L1 engages with PD-1, the T-cell function becomes inhibited; pembrolizumab blocks the PD-1: PDL-1 complex formation, allowing improved T-cell mediated killing[1-2].

Humanised monoclonal antibody:
Treatment of advanced melanoma
Treatment of non-small cell lung carcinoma (NSLC)
Treatment of relapsed or refractory classical Hodgkin lymphoma (cHL)
Treatment of urothelial carcinoma

Besides infusion reactions, most of the adverse events (AEs) are thought to be immune-related AEs. Grade 3–4 AEs only occur in up to 5% of patients. These immune-related AEs can occur in any organ. Because the optimal duration of treatment is undefined, pembrolizumab may be given for up to 2 y. Hence, immune-related AEs can occur late or even after cessation of treatment. To date, cases of rare life-threatening or fatal AEs have been reported after pembrolizumab, including severe skin reactions,80 and fulminant type I diabetes mellitus.81 The frequencies of AEs found in clinical trials are comparable, and are mainly observed when pembrolizumab was used at 10 mg/kg[3].

This humanized receptor-directed monoclonal antibody and anticancer agent (MW = 146.3 kDa; CAS 1374853-91-4), also known by its code name MK-3475, its former name lambrolizumab, and its trade name Keytruda?, targets the Programmed Death-1 (PD-1 or Pdcd1) receptor, a well-known negative regulator of T-cell effector mechanisms that limits immune responses against cancer. Having received "Breakthrough Therapy" designation in April, 2013 to expedite its development as a melanoma therapy, pembrolizumab won final FDA approval in September, 2014. Mechanism of Inhibitor Action: An immunoreceptor belonging to the CD28/CTLA-4 family, PD-1 negatively regulates antigen receptor signaling by recruiting the protein tyrosine phosphatase SHP-2, after interacting with either of two ligands, PD-L1 or PD-L2. With its wide range of ligand distribution in the body, PD-1 is significant in nearly every aspect of immune responses (e.g. autoimmunity, tumor immunity, infectious immunity, transplantation immunity, allergy and immunological privilege). Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. PD-1 and related target PD-ligand 1 (PD-L1) are normally expressed on the surface of activated T cells, and formation of the PDL1·PD-1 complex inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop maintains normal immune responses by limiting T-cell activity and thereby protecting normal cells during chronic inflammation. Tumor cells can circumvent T-cell– mediated cytotoxicity by expressing PD-L1 on their outer surface or on tumor-infiltrating immune cells to inhibit immune-mediated tumor cell killing. Use of pembrolizumab is indicated in the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab, especially if positive for the BRAFV600 mutation. MK3475 is also highly selective, humanized monoclonal IgG4-k isotype antibody against PD-1 that is designed to block the negative immune regulatory signaling of the PD-1 receptor on T cells. Inhibitor Design: To preparepembrolizumab, the variable region sequences of a very high affinity (Kd = 28 pM) mouse anti-human PD-1 antibody were grafted into a human IgG4 immunoglobulin with a stabilizing Ser-228-Pro alteration in Fc receptors. The IgG4 subtype does not engage Fc receptors and does not activate complement, thereby avoiding cytotoxic effects of the antibody when it binds to the T cells that it is intended to activate. Pharmacokinetics: The recommended dose (2 mg/kg) is administered as an intravenous infusion over 30 minutes every 3 weeks, or until disease progression resumes or toxicity becomes unacceptable. Its steady-state concentration is reached by 18 weeks. (Half-life: 26 days; Clearance: 0.22 L/day)

Potentially hazardous interactions with other drugs
Vaccines: risk of generalised infections with live vaccines - avoid.

Pembrolizumab undergoes catabolism to small peptides and single amino acids via general protein degradation routes and does not rely on metabolism for clearance.

Pembrolizumab is a humanized monoclonal IgG4 kappa anti-PD1 antibody. Binding of pembrolizumab to PD1 does not engage Fc receptors or activate complement, so that it is devoid of any cytotoxic activity. The 50% effective inhibitory concentration in T-cell activation assays ranges from 0.1–0.3 nM.32 It is a lyophilized powder, and reconstituted in 0.9% sodium chloride solution to a final concentration of 1–10 mg/mL for intravenous use. It is stable for 4 hours at room temperature, and 24 hours when refrigerated. It is administered as a 30-minute intravenous infusion[3].

[1] “Pembrolizumab Is Safe and Effective in Kaposi Sarcoma.” Cancer discovery (2022): 1183.
[2] Sidaway, Peter. “Pembrolizumab plus chemoradiotherapy effective in locally advanced cervical cancer.” Nature Reviews Clinical Oncology 40 1 (2024).
[3] CADTH, None. “Pembrolizumab (Keytruda).” Canadian Journal of Health Technologies 16 1 (2023): 0.