Cancer immunotherapy is a novel approach which can reverse tumor immune escape by suppressing immune checkpoint pathways. Several immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have demonstrated durable efficacy against melanoma, renal, lung and other cancers. However, despite these promising long-term responses, the majority of patients failed to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of these patients who initially respond to treatment eventually experience relapse secondary to acquired resistance.
At present, researchers have developed two inhibitory approaches including LAG-3 Ig fusion proteins (IMP321) and LAG-3 targeting antibodies. IMP321 developed by Immutep is a soluble forms of LAG-3 which upregulates co-stimulatory molecules and increases interleukin (IL)-12 productions to enhance tumor immune responses. Several LAG-3 targeting monoclonal antibodies have been developed which interferes with the LAG-3 interaction between major histocompatibility complex-II molecules expressed by tumor or immune cells, promoting tumor cell apoptosis. To further enhance the efficacy of LAG-3 targeting drugs, researchers have also established several bispecific antibodies which have enhanced efficacy, specificity, and are cost effective.
There are more than 100 ongoing clinical trials for 35 drugs, which are evaluating the role of LAG-3 inhibitors in wide range of cancers. Relatlimab developed by Bristol Myers Squibb is one of promising LAG-3 targeting antibody which was granted priority review by US FDA for the management of melanoma in combination with Nivolumab. The drug is expected to gain entry in market by 2022, which will revolutionize the paradigm of cancer treatment. Apart from this, several preclinical studies are also evaluating the role of LAG-3 in other therapeutic indications including diabetes, multiple sclerosis, HIV, Parkinson, and other autoimmune disorders.
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