Dostarlimab

Executive Summary:

Dostarlimab is an anti-programmed death-1 (PD-1) monoclonal antibody being developed for the treatment of different cancer types. It is the monoclonal antibody of immunoglobulin G (IgG) 4κ isotype designed to bind to PD-1 while blocking the interaction with its ligands such as PD-L1 and PD-L2.  It originated from the monoclonal antibody of the mouse, which binds and shows inhibition of PD-1 along with blocking the interaction of programmed cell death receptor ligands 1 and 2. The preclinical and clinical research on dostarlimab shows efficacy by binding to either the PD-1 receptor or ligand, blocking the receptor-ligand interaction and showing an antitumor immune response, which improves the survival rate among the patient across different cancer types. This drug was approved in the USA and EU, showing efficacy in treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer. The treatment with the use of dostarlimab is associated with different immune-related adverse reactions that require treatment that can be kept on hold or may be permanently discontinued. Different clinical trials have represented the efficacy of dostarlimab to be used in cancer treatment.

Introduction:

Dostarlimab is an anti-programmed death-1 (PD-1) monoclonal antibody being developed for the treatment of different cancer types, mainly involving endometrial cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), squamous cell cancer (SCC), cancer of the head and neck, and malignant melanoma. It is the monoclonal antibody of immunoglobulin G (IgG) 4κ isotype designed to bind to PD-1 while blocking the interaction with its ligands such as PD-L1 and PD-L2. PD-1 is known as the inhibitory immune checkpoint receptor, which is expressed on activated T cells. PD-1 suppresses the activated effector T-cell functions involving proliferation, cytokine production, and cytotoxic activity by interacting with its programmed cell death ligands 1 and 2 (PD-L1 and PD-L2).

The tumor cells get eliminated from the immune system due to the upregulation of PD-L1, which further interfere with cancer-specific immune responses (Zhang et al., 2009; Chen et al., 2015). Dostarlimab initially originated from the monoclonal antibody of the mouse, which binds and shows inhibition of PD-1 along with blocking the interaction of programmed cell death receptor ligands 1 and 2 (PD-L1 and PD-L2) with the receptor. It restores immune function by activating T cells. In the mouse model, the monoclonal antibody was humanized by grafting the heavy- and light-chain complementarity-determining regions onto the germline variable region frameworks of their closest human species orthologs by affinity maturation through mammalian cell display and somatic hypermutation, using the AnaptysBio SHM-XEL system (Bowers et al., 2011). This model represented antitumor activity assessed by tumor growth inhibition, showing an association with increased infiltration of immune cells. Hence, it reveals that dostarlimab is a potent anti-PD-1 receptor antagonist with properties that support its continued clinical investigation in patients with cancer.

The preclinical and clinical research on dostarlimab shows efficacy by binding to either the PD-1 receptor or ligand, blocking the receptor-ligand interaction and showing an antitumor immune response, which improves the survival rate among the patient across different cancer types. The efficacy of the monoclonal antibody showing the anti-PD-1 mechanism has provided the patients with better survival rates due to the possibility of administering dose regimens while evolving the mechanism of tolerance, treatments related to disease specification, and cost options. But reports have revealed that not all patients have responded to a single treatment representing the requirement of optimized therapeutic agents. The use of dostarlimab is currently being explored for different solid tumor types in the clinical phase trial. The escalation of the dosage and its safety or efficacy is being studied (Subramanian et al., 2020; Davar et al., 2018). 

Dostarlimab is the drug approved in the USA and EU, showing efficacy in treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (FDA, 2021; GlaxoSmithKline, 2021). The dosage recommended for the administration of dostarlimab is 500 mg every three weeks for the first four doses and later, starting with three weeks after the fourth dose, 1000 mg every six weeks until the disease progression or observation of unacceptable toxicity. The treatment with the use of dostarlimab is associated with different immune-related adverse reactions that require treatment that can be kept on hold or may be permanently discontinued. 

Pharmacodynamics

Dostarlimab bounds to human and cynomolgus monkey PD-1 with high affinity as per the action surface plasmon resonance mechanism through flow cytometry using cell lines overexpressing recombinant PD-1 or binding to the native protein on peripheral blood mononuclear cells (PBMC). The mechanism of action of dostarlimab has shown antagonistic behaviour with human CD4+ mixed lymphocyte reaction assay that resulted in higher production of IL-2. The activity of dostarlimab is enhanced in this assay due to the presence of anti-TIM3 or anti-LAG3 antibodies. Incubation of human PBMCs with dostarlimab as a single agent did not induce meaningful stimulation of cytokine release (Laken et al., 2016).  

Pharmacokinetics

The pharmacokinetics of dostarlimab evolves the correlation between Cmax, AUC0−inf and AUC0−τ with increased dosage over the range of 1.0–10 mg/kg among patients with solid tumours, mainly the ones with endometrial cancer. The clinical reports and analysis of Cmax, AUC0−inf and AUC0−τ showed administration of dostarlimab with a dose of 500 mg once every three weeks and later with a dose of 1000 mg once every six weeks. The results with the evaluation of doses of dostarlimab represented no significant differences in its pharmacokinetics depending upon the age, gender, ethnicity, tumor type, or the presence of renal or hepatic impairment of the patient (GlaxoSmithKline, 2021). 

Characterization of Dostarlimab in cancer treatment

The preclinical trial for the efficacy of dostarlimab represented an accurate profile of anti-PD-1 antibody that binds effectively with PD-1 while antagonizing the interaction with PD-L1 and PD-L2. The binding of dostarlimab with high affinity to the human PD-1 receptor is achieved. It shows preclinical efficacy in approving the mechanism of PD-1 therapies, which shows similarity with other drugs such as nivolumab, pembrolizumab, and cemiplimab (Fessas et al., 2017). IgG4 isotype is used for the production of effective modalities. It helps boost the immune response with chronic administration of IgG1 Fc showing mutational changes while introducing immunogenic sites. 

The representation of dostarlimab enhances the T-cell activation in multiple in vitro functional assay systems using primary human T cells. The mechanism of dostarlimab enhanced the T-cell activation within antigen-dependent systems with no direct nonspecific effects on T-cell responses. Also, efficacy in the antitumor activity is represented in humanized mouse tumor models with consistent pharmacokinetic and pharmacodynamic profiles and low potential for off-target effects.

Some side-effects have also been observed due to the increased activation of immune response showing an effective antitumor strategy. Hence, the anti-PD-(L)1 therapy showed adverse responses such as pneumonitis, colitis, hypothyroidism, and infusion-site reactions (Luo et al., 2018). These responses enhance the binding to the target, implicating pharmacodynamic effects involving immune-related adverse events of the anti-PD-(L)1 therapy (Weinmann et al., 2019). The safety and efficacy of dostarlimab are depicted by determining the profile of the new anti-PD-(L)1 therapy. It shows cytotoxic mechanisms due to antibodies binding with the complement or FCγ receptors. Hence, dostarlimab showed very little consistency with no binding to complement protein C1q or Fcγ, the receptors that obtain complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), eventually resulting in the depletion of antitumor effector T cells. 

Features and Properties of Dostarlimab

The below table represents the features and properties of dostarlimab depicted in various studies:

Chemical nameImmunoglobulin G4, anti-programmed cell death protein 1 (PDCD1) (humanized clone ABT1 gamma4-chain), disulfide with humanized clone ABT1 kappa-chain, dimer
Alternative namesJemperli™, TSR 042, GSK-4057190, ANB 011, WBP 285
ClassAntineoplastics, immunotherapies, monoclonal antibodies
Action mechanismProgrammed cell death-1 receptor antagonist
Route of administration IV
PharmacodynamicsBinding with  high affinity to human programmed cell death-1 receptor
PharmacokineticsAnalysis of Cmax, AUC0−inf and AUC0−τ  with dose of  500 mg every 3 weeks for the first four doses and later, starting with 3 weeks after the fourth dose, 1000 mg every 6 weeks until the disease progression or observation of unacceptable toxicity.
Common side effectsAnaemia, hypothyroidism, nausea, diarrhoea, vomiting, pruritus, rash, arthralgia, pyrexia, increased transaminase levels
Occasional side effectsAdrenal insufficiency, pneumonitis, colitis, pancreatitis, chills, infusion related reactions
Rare side effectsType 1 diabetes mellitus, diabetic ketoacidosis, uveitis, hepatitis, nephritis

Clinical Trials of Dostarlimab

Several clinical trials have been conducted to determine the efficacy of dostarlimab in cancer treatment. GARNET trial (NCT02715284) with single-group phase I was conducted for endometrial cancer. It involved the patients with recurrent or advanced tumors who had undergone platinum-based doublet chemotherapy and were treated with dostarlimab at the recommended dose. The patients were monitored for ≥ 6 months follow up. The result showed nine complete, confirmed, and 21 partial responses (Oaknin et al., 2020). Another clinical trial with Cohort F of GARNET involved the patients having gastrointestinal tumours. Overall confirmed response was observed among the patients with administration of dostarlimab with a follow-up of 12.4 months (Andre et al., 2021). The NSCLC expansion cohort of the GARNET study was also conducted with patients with recurrent or advanced NSCLC showing a confirmed immune-related overall response rate with a follow-up of 11.6 months (Subramanian et al., 2020).

AMBER (NCT02817633) trial with ongoing phase I A was evaluated involving the combination therapy with dostarlimab and the anti-TIM-3 antibody cobolimab (TSR-022) among the patients having NSCLC. The result showed objective responses and stable disease, representing the potential for biomarker enrichment (Davar et al., 2018). The open-label multipart phase I IOLite trial (NCT03307785) is another clinical trial involving the combination treatment of dostarlimab with recommended doses. This clinical trial is carried out in four major subparts. Part A evaluates the dostarlimab in combination with niraparib, part B evaluates dostarlimab combined with carboplatin-paclitaxel, and part C involves the combination of dostarlimab with niraparib and bevacizumab and part D involves the combination of dostarlimab with carboplatin-paclitaxel and bevacizumab (Gabrail et al., 2019).

References

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  4. Food & Drug Administration. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [media release]. 22 Apr 2021. https://www.fda.gov/drugs
  5. GlaxoSmithKline. European Commission approves GSK’s JEMPERLI (dostarlimab), the frst anti-PD-1 therapy approved for recurrent or advanced endometrial cancer [media release]. 23 Apr 2021. https://www.gsk.com.
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