PD-L1 inhibitors are a group of novel drugs that act to inhibit the association of the programmed death-ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1). The interaction of these cell surface proteins is involved in the suppression of the immune system and occurs following infection to limit the killing of bystander host cells and prevent autoimmune disease. This immune checkpoint is also active in pregnancy, following tissue allografts and in different types of cancer.
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Cancer immunotherapy
In the cancer disease state the interaction of PD-L1 on the tumour cell surface with PD-1 on a T-cell reduces T-cell function signals to prevent the immune system from attacking the tumour cells. Use of a PD-L1 inhibitor that blocks the interaction of PD-L1 with the PD-1 receptor can prevent the cancer from evading the immune system responses in this way. Several PD-L1 inhibitor antibodies are being successfully trialled within the clinic for use in advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other cancer types.
Immunotherapy with these immune checkpoint inhibitors appears to shrink tumours in a higher number of patients across a wider range of tumour types and is associated with lower toxicity levels than other immunotherapies. Compared to the acknowledged ceiling of 10% patient response rates for previous immunotherapy approaches to cancer, treatment with PD-L1 inhibitors are showing responses in between 25 and 40% of patients. One of the most notable features of immune checkpoint inhibition appears to be the durability of the patient response, with patients living much longer than with other standard cancer treatments, such as chemotherapy. Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.
Smaller tumours appear to respond better to anti-PDL1 therapy and so the best results may be achieved by using PD-L1 inhibitors as part of a combination of therapies, with radiotherapy or chemotherapy. Part of the issue may be the large size of the antibody being unable to penetrate solid tumours to take effect. Shrinking the tumour with other approaches before immune checkpoint immunotherapy could avoid this. Additionally, treating patients firstly with radiation or chemotherapy may release tumour antigens from the dead tumour cells, making the tumour more visible to the immune system.
Therapeutics
Few PD-L1 inhibitors have been approved for use to date, though extensive target validation has been shown through phase II and III clinical trials using different monoclonal antibody therapies.
The PD-L1 inhibitor atezolizumab (MPDL3280) is a fully humanised, engineered, IgG1 antibody developed by Roche Genentech. It has shown promising results in Phase I trials in the treatment of a number of different cancers, including melanoma, lung, bladder and renal cancer. Atezolizumab in the treatment of urothelial bladder cancer has completed phase II trials. Phase II and III trials of this compound in the treatment of non-small cell lung cancer are now underway and a decision from the FDA is expected later in 2016 regarding the drug’s approval.
In May 2016 FDA granted accelerated approval to atezolizumab for locally advanced or metastatic urothelial carcinoma treatment after failure of chemo or radio therapy.
Avelumab (MSB0010718C) is a fully human IgG1 antibody developed by Merck KGaA and Pfizer. It has completed Phase I trials for metastatic or locally advanced solid tumours. Phase II trials have been reached for Avelumab in the treatment of Merkel-cell carcinoma and Phase III trials have been reached for this drug in the treatment of non-small cell lung cancer.
Durvalumab is an anti-PD-L1 antibody developed by AstraZeneca. Phase III trials for the treatment of metastatic urothelial bladder cancer in combination with an alternative immune checkpoint inhibitor have been reached.
Alternatives to antibodies
The drawbacks associated with antibodies include their large size and their ability to activate antibody dependent cell-mediated cytotoxicity, through their Fc-region. While Fc-mediated effects are an important part of the efficacy of many antibody therapeutics, in the case of PD-1 / PD-L1 inhibition this may be counterproductive. Smaller engineered affinity proteins offer a potentially more effective alternative to antibody therapeutics as PD-L1 inhibitors.
Avacta Life Sciences are developing a PD-L1 inhibitor to meet this need. It is based on their engineered Affimer protein scaffold. The use of a smaller inhibitor should improve diffusion of the therapeutic throughout solid tumours. Multimeric Affimer biotherapeutic formats can also be engineered to create bi-specific molecules that combine two different immune checkpoint inhibitors to improve efficacy and offer a better clinical outcome for the patient.