The landscape for new biologics formats
Dr Jane Osbourn, VP Research and Development and Site Leader, MedImmune
Antibody engineering has come of age and there are now over 500 antibody therapeutics in clinical development and nearly 70 approved for a wide range of different disease indications. Amongst these, there are many examples of antibodies with engineered properties such as increased potency, half-life extension and improved stability. The landscape for biologics therapies is evolving to deliver additional functionality with the introduction of novel formats, such as bispecific antibodies, peptide-antibody fusions, scaffolds and antibody -drug conjugates. Case studies will be presented illustrating the benefits of different formats and how they can be applied in different disease settings.
Antigen-targeted TCRs in cancer immunotherapy
Dr Bent Jakobsen FMedSci, Chief Scientific Officer, Immunocore
Cancer immunotherapies function to harness the body’s own immune system to eradicate cancer cells. Critical to this process is the T cell, capable of directing potent and antigen-specific immune responses. T cell receptor (TCR) antigens are short intracellularly processed peptides presented on the cell surface, offering distinct advantages over antibody-based therapies that recognise secreted or cell surface proteins. Here, we describe two novel platforms designed to overcome the limitations of the natural T cell response to deliver high-affinity engineered TCRs to an identified and validated target antigen. The platforms can be distinguished based on a cellular versus soluble approach. SPEAR (Specific Peptide Enhanced Affinity Receptor) T cell therapies targeting MAGE-A10, MAGE-A4, AFP and NY-ESO are progressing through clinically studies in multiple solid and hematologic cancers. The lead soluble ImmTAC® (Immune mobilising monoclonal TCR against cancer) molecule, IMCgp100, has entered pivotal monotherapy trials for the treatment of patients with metastatic uveal melanoma.
Antisense oligonucleotide therapy for Huntington's disease - results from the first HTT lowering clinical trial
Professor Sarah J Tabrizi FMedSci, Director of UCL Huntington's disease centre, UCL Institute of Neurology
Authors: Sarah J Tabrizi, Blair Leavitt, Bernhard Landwehrmeyer, Edward Wild, Carsten Saft, Roger Barker, David Craufurd, Josef Priller, Hugh Rickards, Anne Rosser, Holly Kordasiewicz, Christian Czech, Eric Swayze, Daniel A. Norris, Tiffany Baumann, Irene Gerlach, Scott Schobel, Anne Smith, Roger Lane, C. Frank Bennett - on behalf of the study teams
Background: HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A comprehensive drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production.
Design/Methods: In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx (RG6042) or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent Data Safety Monitoring Board review of safety, PK and target engagement prior to dose escalation.
Results: IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mHTT were observed.
Conclusions: ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD.
Study Supported By: Ionis Pharmaceuticals
Dr Kristoffer Famm, President, Galvani Bioelectronics