Volrustomig, also known as MEDI5752 is a bispecific antibody developed by the AstraZeneca, that targets programmed death 1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). This dual targeting bispecific antibody has the potential to enhance the therapeutic benefit and decrease the risk of toxicity which is typically associated with CTLA-4 inhibitors. Monoclonal antibodies targeting the immune checkpoint proteins such as the PD-1 and CTLA-4 have been around for a long time, however, due to their limited effect of majority of patients, the idea of dual immune checkpoint inhibitors using bispecific antibodies has been gaining attention from researchers all over the world.
Several studies have suggested that the dual expression of PD-1 and CTLA-4 checkpoint proteins is feature of the tumor microenvironment (TME). The mechanism of action of Volrustomig is based on the simultaneous and dual targeting of programmed death 1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). On administration, the bispecific antibody binds and targets PD-1 and CTLA-4 receptors which are expressed on tumor infiltrating lymphocytes (TILs) and inhibit their function of down regulating the T cell activation and proliferation.
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Additionally, this bispecific antibody Volrustomig is internalized and is capable to degrade programmed death 1 (PD-1) which restores the immune system’s function and activates a constant CTL (cytotoxic T lymphocyte) facilitated immune response against the cancerous cells. Both the targeted immune checkpoint proteins, PD-1 and CTLA-4 are expressed on tumor infiltrating lymphocytes and actively down regulate the activation and effector functions of T lymphocytes which help tumor cells to evade the host’s immune system.
The dual blockade of immune checkpoints PD-1 and CTLA-4 with Volrustomig might improve T cell activation and proliferation more in comparison to either immune checkpoint blocked alone. This might also decrease the toxicity by avoiding the binding to CTLA-4 expressed on T cells which are lacking PD-1 expression. AstraZeneca has initiated several late stage clinical trials for its high potential medicines that include Volrustomig.
Currently, this bispecific antibody is being investigated in 9 clinical trials for advanced renal cell carcinoma and advanced solid tumors in combination several other anti-cancer therapeutic agents. For instance, a phase I clinical trial is evaluating Volrustomig (MEDI5752) in combination with Axitinib and Lenvatinib, both of which are kinase inhibitors for the treatment of patients with advanced renal cell carcinoma. The aim of the study is to evaluate Volrustomig in combination with kinase inhibitors. This phase Ib study will evaluate the tolerability, safety, pharmacokinetics, anti-tumor activity and immunogenicity of Volrustomig in a combinational regimen.
The primary objective will be measure in terms of number of patients experiencing adverse events (AEs), dose limiting toxicities (DLT), and preliminary anti-tumor activity of Volrustomig among other criteria. While the second objective is to measure the progression free survival (PFS) of the combinational therapy, best overall response (BOR), disease control rate (DCR), duration of response (DOR), time to response (TTR), pharmacokinetics and immunogenicity of Volrustomig.
Apart from there is another clinical trial, investigating Volrustomig in combination with different chemotherapeutic drugs such as Pemetrexed, Carboplatin, Paclitaxel or nab- paclitaxel and pembrolizumab. This phase I clinical study is a first in human, dose escalation and dose expansion study in patients with advanced solid tumors when administered as a monotherapy or in combination with chemotherapy.
Primary outcomes of the study will be measured in terms of adverse events, preliminary anti-tumor activity of Volrustomig in comparison with Pembrolizumab determined by objective response rate (ORR), dose limiting toxicities (DLT), number of patients experiencing abnormal electro cardiograms (EGC) and treatment related serious adverse events (SAEs). Whereas, secondary outcomes include pharmacokinetics in different time frames, ability of Volrustomig to generate immune response, endpoint for the PD- L1 expression, preliminary anti-tumor activity, progression free survival (PFS), overall survival (OS) and number of patients experiencing treatment related serious adverse events (SAEs) in the dose expansion part of the clinical study.
Contact:
Neeraj Chawla
Kuick Research
Research Head