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Interested in studies of the adaptive immune receptor repertoire (AIRR)? Catch up on the latest in this new episode of On AIRR – An AIRR-C Podcast Series. Dr. Ulrik Stervbo and Dr. Zhaoqing Ding sit down with Vadim Nazarov the Co-Founder & CEO of the startup ImmunoMind to discuss the use of AI for repertoire insights.
Check out On AIRR Podcast #9 The ImmunoMind or wielding an AI for repertoire insights with Vadim Nazarov.
On November 17, 2022, the US Food and Drug Administration (FDA) approved TZIELD™ (teplizumab-mzwv) to delay the onset of Stage 3 type 1 diabetes (T1D) in adult and pediatric patients aged 8 years and older with Stage 2 T1D. The approval was based in part on a clinical trial in Stage 2 T1D patients in which TZIELD delayed the median onset of Stage 3 T1D by 25 months, or approximately 2 years, compared to placebo.
Teplizumab is a humanized, anti-CD3e IgG1k antibody originally developed at Tolerance Therapeutics, Inc. and the University of California. The antibody Fc region was mutated (L234A; L235A) to reduce effector functions. Teplizumab binds CD3 expressed on mature T cells and may induce expansion and/or regulatory function in T cell subsets. In 2005, teplizumab was licensed to MacroGenics. In 2018, Provention Bio acquired all rights to teplizumab and subsequently continued its development for the prevention and treatment on T1D. The FDA granted teplizumab Orphan Drug designation for the treatment of recent-onset T1D. Teplizumab was also granted FDA’s Breakthrough Therapy designation for the prevention or delay of clinical T1D in at-risk individuals and EMA’s PRIority MEdicines (PRIME) designation for the same indication. As of October 2022, Provention Bio and Sanofi had entered into a co-promotion agreement for teplizumab.
Provention Bio is currently evaluating teplizumab in patients with newly diagnosed insulin-dependent T1D in the global PROTECT (PROvention T1D trial Evaluating C-peptide with Teplizumab) Phase 3 study (NCT03875729). This randomized, double-blind, placebo-controlled, multicenter trial will enroll 300 patients with recent onset T1D who will be randomized 2:1 to either two 12-day cycles of teplizumab (IV) or placebo. The primary efficacy endpoint is C-peptide change. Secondary endpoints include insulin use, HbA1c, hypoglycemic episodes, and safety. The company expects top line data from PROTECT Phase 3 study in 2H 2023.
The US Food and Drug Administration (FDA) granted an accelerated approval for mirvetuximab soravtansine-gynx (ELAHERE™) for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens, on November 14, 2022. FDA also approved a companion diagnostic, VENTANA FOLR1 (FOLR1-2.1) RxDx Assay, developed by Roche.
Mirvetuximab soravtansine, developed by ImmunoGen as a treatment for epithelial malignancies such as ovarian adenocarcinoma, is an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα). The cytotoxic warhead, the tubulin-targeting maytansinoid drug DM4, is conjugated to the humanized IgG1ҡ antibody via a cleavable disulfide linker. The ADC has been granted Orphan Drug designations for ovarian cancer in the US and EU, and FDA’s Fast Track designation for a specific subset of ovarian cancer patients with medium to high FRα-positive platinum-resistant lesions who received between one and three prior systemic treatments, and for whom single-agent chemotherapy is appropriate as the next line of therapy.
FDA’s approval was based on positive results of the Phase 3 SORAYA study (NCT04296890), which evaluated the efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant advanced high-grade epithelial ovarian, primary peritoneal or fallopian tube cancer, whose tumors express a high-level of FRα. A total of 106 platinum-resistant ovarian cancer patients with high FRα expression previously treated with at least one, but less than three prior systemic treatments, at least one of which included bevacizumab, received mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) administered on day 1 of every 3-week cycle. Results from the SORAYA trial were presented at the Society of Gynecologic Oncology (SGO) annual meeting held in March 2022. Additional efficacy analyses based on a 120-day cut-off date showing tumor reduction in 71.4% of patients, an objective response rate of 32.4% as assessed by the investigator, and a preliminary median OS of 13.8 months were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held June 3-7, 2022. A retrospective safety analysis based on 464 patients with FRα positive, recurrent ovarian cancer pooled across three studies (a Phase 1 first-in-human trial and the Phase 3 FORWARD I and SORAYA trials) demonstrating a differentiated and consistent safety profile was also presented at the 2022 ASCO meeting.
Mirvetuximab soravtansine was also evaluated in the randomized Phase 3 FORWARD I trial (NCT02631876), which enrolled 366 patients with platinum-resistant ovarian cancer, randomized 2:1 to receive either the ADC or the physician’s choice of pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel. Improved patient-reported outcomes associated with mirvetuximab compared with chemotherapy were presented at the European Society for Medical Oncology (ESMO) in held in Paris, France in September 2022. In addition, ImmunoGen continues to enroll patients in the randomized, open-label Phase 3 MIRASOL study (NCT04209855), which is evaluating mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Top-line data from the confirmatory MIRASOL study are expected to be announced in early 2023. If positive, the results may support a full approval by FDA.
Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.
Adaptive immune receptor repertoires (AIRRs) capture past and present immune responses and therefore represent a powerful resource for developing diagnostics and therapeutics. Machine learning (ML) has the ability to discover complex sequence patterns and help further these diagnostic and therapeutic aims. However, to exploit these opportunities, it is necessary to overcome the intrinsic challenges of AIRR data: unknown rules determining antigen binding, high diversity and specificity of receptors with low overlap between AIRRs, and low signal-to-noise ratio. Further, different ML approaches need to be validated and compared before they could be deployed in practice. In this webinar, we will focus on standardized and reproducible ML workflows, benchmarking, and comparison of AIRR ML approaches. We will argue for the use of simulation for validation and benchmarking of ML methods before moving to experimental datasets.
Maria Chernigovskaya is a PhD candidate supervised by Prof. Victor Greiff and Prof. Geir Kjetil Sandve at the University of Oslo, Norway. Maria is working on a methodology for simulating synthetic adaptive immune receptor repertoire (AIRR) datasets to guide the development and benchmarking of AIRR-based machine learning.
Milena Pavlović is a postdoctoral researcher in the Sandve lab at the University of Oslo working on machine learning, causal inference, and their application to biomedical domains. During her PhD, Milena developed the immuneML platform (https://immuneml.uio.no) for the analysis of adaptive immune receptors and repertoires (AIRR), focusing on model robustness and reproducibility, and examined how the knowledge of the data generating process and the causal inference framework could improve AIRR machine learning diagnostics.
The European Commission (EC) has approved AstraZeneca and Sanofi’s Beyfortus® (nirsevimab) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season. Nirsevimab is human IgG1ҡ antibody targeting RSV. The Fc domain was engineered using AstraZeneca’s proprietary YTE half-life extension technology. Developed by AstraZeneca and Sanofi, nirsevimab is designed to offer newborns and infants direct protection against RSV and help prevent RSV-related lower respiratory tract infections.
Nirsevimab received regulatory designations to facilitate development, including a Promising Innovative Medicine designation from the UK Medicines and Healthcare Products Regulatory Agency; Breakthrough Therapy designation from China’s NMPA; Breakthrough Therapy designation from FDA; and PRIME designation from EMA. In addition, it was named “a medicine for prioritized development” under the Project for Drug Selection to Promote New Drug Development in Pediatrics by Japan’s Agency for Medical Research and Development. The approval by the EC was based on results of the Phase 3 MELODY (NCT03979313), Phase 2/3 MEDLEY (NCT03959488), and Phase 2b (NCT02878330) clinical trials.
The Phase 2b trial is a randomized, placebo-controlled trial designed to measure the efficacy of nirsevimab in preventing medically attended RSV-related lower respiratory tract infections through 150 days post-dose. The study was conducted on healthy preterm infants (29–35 weeks’ gestation) who were randomized (2:1) to receive a single intramuscular injection of nirsevimab (50 mg) or placebo. The primary endpoint of the study was met, with a reduction of the incidence of medically attended RSV-related lower respiratory tract infections by 70.1% (95% CI: 52.3, 81.2) compared to placebo.
MELODY is a randomized, placebo-controlled Phase 3 trial evaluating the safety and efficacy of nirsevimab for the prevention of medically attended lower respiratory tract infections in healthy late preterm and term infants (i.e., born at 35 weeks’ gestation or later). Participants (n=1490) up to 1 y of age were randomized (2:1) to receive a single intramuscular injection of nirsevimab (50 mg if <5 kg or 100 mg if >5 kg body weight) or placebo. The primary endpoint of this study was met, with a reduction in the incidence of medically attended lower respiratory tract infections caused by RSV of 74.5% (95% CI 49.6, 87.1; P<0.001) compared to placebo.
The randomized, double-blind, palivizumab-controlled Phase 2/3 MEDLEY study evaluated the safety and pharmacokinetics of nirsevimab compared to palivizumab in preterm infants and infants with congenital heart disease and/or chronic lung disease of prematurity eligible to receive palivizumab entering their first RSV season. Participants (n=925) up to 1 year of age entering their first RSV season were randomized to receive a single intramuscular injection of nirsevimab or palivizumab (50 mg if <5 kg or 100 mg if >5 kg body weight). Safety was assessed by monitoring the occurrence of treatment-emergent adverse events or treatment-emergent serious adverse events through 360 days post-dose. Serum levels of nirsevimab following dosing (on day 151) in this trial were comparable with those observed in the MELODY study, suggesting a similar protection in this population to that in the healthy term and late preterm infants.
