Re-engineering proteins to develop novel immunotherapies
Posted: 13 July 2023 | Jessicca Rege (Alkermes) |
Jessicca Rege of Alkermes gives insights into how protein engineering approaches have led to the event of novel therapies that harness the immune system’s capabilities to combat most cancers.
The sector of immunotherapy is continually evolving with the last word objective to develop new remedies that assist the physique’s immune system combat most cancers. Immune cells, corresponding to T cells and pure killer (NK) cells, have the inherent potential to fight illnesses, together with most cancers, however are sometimes inhibited by the physique’s personal suppressive mechanisms. Most cancers immunotherapies corresponding to checkpoint inhibitors (CPIs) have been designed to counteract these. Right now, there are a lot of authorised immunotherapy approaches that may improve the anti-tumour exercise of immune cells, leading to improved survival charges. Nevertheless, whilst science advances, there stay sufferers who nonetheless want new therapy choices. By re-engineering current approaches which have already proven medical promise, there’s potential to deliver additional profit to the affected person neighborhood in its combat towards most cancers.
Unlocking the potential of immunotherapies
Many years in the past, antibodies focusing on the protein CD20, discovered on B cells, revolutionised the best way we deal with some leukaemias and lymphomas. Since then, a number of next-generation antibodies have been engineered with modifications that allow them to raised have interaction with immune cells.1 For instance, the antibody obinutuzumab was engineered with modified sugars on the fragment crystallisable (Fc) portion of the antibody, offering higher potential to induce anti-tumour efficacy. A brand new therapeutic antibody class, bispecific antibodies, was engineered to construct on the traditional antibody design and bind to 2 completely different proteins, demonstrating how incremental modifications in protein design can result in solely new therapies.2
One other immunotherapy therapy possibility, CAR T-cell remedy, includes accumulating a affected person’s T cells and engineering them to provide floor proteins often called chimeric antigen receptors (CARs).3 The CARs recognise and bind to proteins on the floor of most cancers cells, successfully killing them. CAR T-cell therapies have been authorised to deal with a number of most cancers sorts, together with blood cancers corresponding to lymphomas, a number of myeloma and a few leukaemias. Nevertheless, to this point its software for stable tumours has been difficult. Moreover, CAR T-cell therapies have to be customised for every affected person, doubtlessly making remedy entry difficult. To deal with this, a number of firms are investigating superior biomedical engineering strategies, corresponding to CRISPR, to generate novel CAR T-cell therapies with shorter wait occasions.4
Harnessing the ability of cytokines
Cytokines are immune-signalling proteins which have lengthy proven promise as a therapeutic possibility for a lot of illnesses together with most cancers. An artificial model of the cytokine interleukin-2, or IL-2, recognized for its potent results on immune cells, was authorised to deal with metastatic melanoma and kidney most cancers greater than 20 years in the past – making it the primary authorised immuno‑oncology therapy. Though IL-2 was recognised as an efficacious therapy, medical use was restricted by toxicity points. IL-2 remedy is related to security considerations, particularly the opposed occasion capillary leak syndrome, which regularly results in hospitalisations and thus limits its medical use. As well as, excessive doses of native IL-2 can activate suppressive immune cells that counteract the anti‑tumour results of CD8 T cells and NK cells.5
With the arrival of recent protein engineering capabilities and the growing understanding of the immune system, researchers at the moment are capable of design cytokines meant to mitigate a few of these points. The sector of IL‑2‑based mostly immunotherapy is an instance of such novel design approaches.
Challenges of protein engineering
A number of firms have targeted on growing investigational IL-2 therapies, utilising superior applied sciences to re‑engineer the IL-2 protein to retain its anti-tumour results whereas minimising security considerations. Protein engineering comes with a number of challenges, together with sustaining stability and immunogenicity of the novel protein and creating an inherently lively drug. Some approaches have relied on introducing chemical entities to the IL-2 protein, with the objective to direct its exercise solely in direction of most cancers‑preventing immune cells. Others have modified IL-2 to be administered as a prodrug that’s activated contained in the physique by way of metabolic cleavage. Whereas these approaches have validated the potential of IL-2 as an immunotherapy, full medical growth has been hindered by suboptimal information in medical trials, additional underscoring the challenges of successfully re-engineering this molecule.
Moreover, medical trials of novel immunotherapies, together with IL-2–based mostly therapies, are sometimes designed utilizing combos with immune checkpoint blockade, making it tough to isolate monotherapyactivity of the investigational agent. Institution of single-agent exercise is a important part to think about within the growth of recent medicine, as eliciting the part impact of every molecule (in a mix) is important in medical growth and, in the end, regulatory approval.
At Alkermes, we have now taken a novel method to redesigning IL‑2. Our investigational IL-2 remedy nemvaleukin alfa (nemvaleukin), is an engineered fusion protein developed by fusing a modified IL-2 protein with a subunit of its personal receptor, the excessive‑affinity IL-2 receptor alpha chain.6 This molecule was designed with the objective of retaining anti-tumour exercise of IL-2 and preferentially increasing anti‑tumour immune cells (T cells and NK cells) whereas mitigating potential drawbacks of high-dose native IL-2 that result in immunosuppression and toxicity. The molecule is a steady fusion protein that’s administered as an lively drug and doesn’t degrade into native IL-2 contained in the physique. Early medical trials have demonstrated medical exercise of nemvaleukin in sufferers pretreated with CPIs, as monotherapy, and together with pembrolizumab in tumour sorts, together with these which are authorised and unapproved for pembrolizumab therapy.
Protein engineering comes with a number of challenges, together with sustaining stability and immunogenicity of the novel protein and creating an inherently lively drug
In these early research, notably encouraging outcomes have been seen in mucosal melanoma and platinum-resistant ovarian most cancers (PROC), that are each difficult-to-treat tumour sorts. Information from these early research have paved the best way for ongoing, later-phase medical trials in mucosal melanoma and PROC. Nemvaleukin is being investigated as a monotherapy for sufferers with mucosal melanoma who progressed on immune CPIs, and for PROC as monotherapy and together with pembrolizumab. Nemvaleukin acquired a number of regulatory designations for growth programmes from the US Meals and Drug Administration (FDA) in 2021: Orphan Drug Designation and Quick Observe Designation for mucosal melanoma and Quick Observe Designation for the therapy of PROC. Moreover, nemvaleukin acquired entry into the Progressive Licensing and Entry Pathway (ILAP) within the UK earlier this 12 months for the therapy of mucosal melanoma.
Re-engineered immunotherapies: a turning level for immuno-oncology
Re-engineered immunotherapies have the potential to offer new therapy choices in oncology that will assist broaden the vary of cancers and the affected person inhabitants that may be handled with these therapies. As continued analysis deepens our understanding of protein engineering and the immune system, we are going to proceed to work relentlessly to develop new therapy choices for oncology sufferers with difficult-to-treat tumour sorts.
Concerning the creator Jessicca Rege, PhD serves as Vice President, Scientific Analysis Oncology at Alkermes, the place she is answerable for establishing the corporate’s immuno-oncology growth technique and overseeing the execution of its international medical trials. Dr Rege joined Alkermes in 2020, bringing along with her greater than 15 years of expertise in analysis, medical growth and international medical affairs. She beforehand held roles of accelerating accountability at Bristol-Myers Squibb, Eisai, Daichi Sankyo and Boehringer Ingelheim. Dr Rege earned a Bachelor of Science from Carson-Newman, and holds each a Grasp of Science in Physiology and a PhD in Pharmaceutical Sciences from Virginia Commonwealth College. She accomplished her postdoctoral fellowship in paediatric leukemia on the College of Pennsylvania’s Youngsters’s Hospital of Philadelphia.