Lambrolizumab: Mechanism, Bioactivity and Toxiological Studies

General description

The lambrolizumab, previously known as MK-3475, with the CAS No: 1374853-91-4, is an antibody against the programmed death 1 (PD-1) receptor. And it is a humanized monoclonal IgG4-kappa isotype antibody designed to block the negative immune regulatory signaling of the PD-1 receptor expressed by T cells. lambrolizumab monoclonal antibodies have activity against several solid tumors and have activity against several solid tumors. Pembrolizumab, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma.[5] Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti–PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies.[4]

Figure 1 The lambrolizumab tablet

Pharmacodynamics

lambrolizumab can be used to treat patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab (Yervoy) and those who had not, were given lambrolizumab intravenously at a dose of 10 mg/kg every 2 or 3 weeks or 2 mg/kg every 3 weeks in light of clinical study. The confirmed response rate across all dose cohorts was 38% (95% confidence interval [CI]=25–44), with the highest confirmed response rate observed in the 10 mg/kg every 2 weeks cohort (52%; 95% CI=38–66). “The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate = 38% [95% CI=23–55] and 37% [95% CI=26–49], respectively),” the investigators observed.[2]

Peak-level and trough-level blood samples for pharmacokinetic analysis were obtained from patients at the initiation of treatment. Trough samples were also obtained approximately every 12 weeks for the first 12 months of the study and every 6 months thereafter. The serum concentration of lambrolizumab was quantified with the use of a validated electrochemiluminescent assay with a lower limit of quantification of 10 ng per milliliter. Serum concentrations of lambrolizumab in samples obtained before and after administration of the drug were lower by a factor of approximately 5 in patients receiving 2 mg per kilogram every 3 weeks than in those receiving 10 mg per kilogram every 3 weeks; steady-state trough concen-trations were 20% greater in the patients receiving 10 mg per kilogram every 2 weeks than in those receiving the same dose every 3 weeks. The increase in trough serum concentrations over time is consistent with the half-life of lambrolizumab of about 2 to 3 weeks. The results of the previous experiment showed that lambrolizumab was safe at the dose levels tested (1 mg per kilogram of body weight, 3 mg per kilogram, and 10 mg per kilogram, administered every 2 weeks) with out reaching a maximum tolerated dose. In addition, clinical responses were observed at all the dose levels.[3] Previous clinical cases report proved that the patient with stage IV, M1c melanoma inthe lung, liver, subcutaneous soft tissue, and inguinal lymph nodes without a BRAF(v-raf murine sarcoma viral oncogene homolog B) gene mutation, had a partial re-sponse with improvement in the pulmonary nodules, stable liver metastases, and a decrease in size of the inguinal and subcutaneous masses after four cycles of treatment by single-agent lambrolizumab.[1] Antibodies blocking PD-1 and PD-L1 have revolutionized the management of metastatic melanoma. There is emerging evidence that combining the PD-1 blocking therapies with other immunotherapies will result in improved results compared to single-agent activity.[4]

Mechanism of action

For lambrolizumab: Biopsied specimens of regressing lesions were densely infiltrated by CD8+ cytotoxic T lymphocytes and releasing inhibitory immune regulation by PD-1 for effective antitumor immunity.[3]

Toxicity

A Phase I/II study examining the safety of lambrolizumab in 135 pa-tients found that 79% reported drug-related adverse events ofany grade and 13% reported grade 3 or 4 drug-related adverse events. Themost common toxicities observed included fatigue, rash, diarrhea, nausea, cough, and itching. Other noted side effects are hypothyroidism, ab-dominal pain, myalgia, headache, asthenia, chills, decreased appetite, pyrexia, elevated transaminases, renal failure, dyspnea, pneumonitis, and vitiligo. Seven lambrolizumab-related Grade 3/4 adverse events were reported as potentially“immune related”. None of the adverse events suspected to be of an inflammatory or autoimmune nature were reported to affect the central nervous system.[1] Thus,we can know that Common adverse events of lambrolizumab attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade,” the authors reported.[2]

References

1. Mandel J J, Olar A, Aldape K D, et al. Lambrolizumab induced central nervous system (CNS) toxicity[J]. Journal of the Neurological Sciences, 2014, 344 (1-2): 229-231.

2. Bath C. Anti-PD-1 Antibody Lambrolizumab Produces Durable Responses with Low Toxicity in Patients with Advanced Melanoma[J]. 2013.

3. Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma[J]. Massachusetts Medical Society, 2013, 2.

4. Homet Moreno B, Parisi G, et al. Anti–PD-1 Therapy in Melanoma[J]. Seminars in Oncology, 2015, 42(3):466-473.

5. Karim S,  Leighl N. Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions[J]. Future Oncology, 2016, 12(1).