Prof Katalin Karikó: mRNA technology a versatile tool to transform the future of medicine

At an honorary degree conferment ceremony held at the Chinese University of Hong Kong and an interview with MIMS Doctor, Professor Katalin Karikó, a pioneer of mRNA technology, suggested that recent advances in mRNA research can provide a versatile tool for combating various diseases.

“Right now, there are >150 ongoing clinical trials of mRNA-based vaccines and therapies, compared with only six trials before 2020,” Karikó highlighted. “I believe that mRNA technology will transform the future of medicine.”

Cancer therapy

“In the ongoing, randomized, phase II [KEYNOTE-942] trial, mRNA-4157 plus pembrolizumab showed significant clinical benefits in patients with high-risk melanoma after resection,” Karikó said. [Khattak A, et al, ASCO 2023, abstract LBA9503]

mRNA-4157 is a personalized neoantigen therapy that targets tumour-specific mutational signatures. In KEYNOTE-942, patients with resected stage IIIB–IV cutaneous melanoma were randomized to receive mRNA-4157 plus pembrolizumab (n=107) or standard-of-care pembrolizumab (n=50). mRNA-4157 1 mg was administered intramuscularly Q3W for ≤9 doses, while pembrolizumab 200 mg was given intravenously Q3W for ≤18 doses.

At a median follow-up of 2 years, adding mRNA-4157 to pembrolizumab reduced the risk of recurrence or death by 44 percent (hazard ratio [HR], 0.561; 95 percent confidence interval [CI], 0.309–1.017; p=0.0266) and the risk of distant metastasis or death by 65 percent (HR, 0.347; 95 percent CI, 0.145–0.828; p=0.0063). (Table)

Another ongoing phase I/II trial in patients with claudin 6–positive advanced solid tumours evaluates the efficacy and safety of treatment with BNT142, a platform that employs lipid nanoparticle (LNP)–encapsulated RNAs encoding T-cell–engaging bispecific antibody. A preclinical trial in mice demonstrated that BNT142 eliminated xenograft tumours as effectively as the corresponding purified antibody. [Yap TA, et al, ASCO 2023, abstract TPS2669; Nat Med 2017;23:815-817]

Rare disease: hATTR

“[According to an early-phase trial,] a single [intravenous] infusion of CRISPR–Cas-9 therapy involving LNP-encapsulated mRNA [ie, NTLA-2001] reduced levels of misfolded transthyretin [TTR] protein in patients with hereditary TTR-mediated [hATTR] amyloidosis,” noted Karikó.

NTLA-2001 includes an LNP delivery system with a single guide RNA targeting human TTR gene and a human codon–optimized mRNA sequence of Streptococcus pyogenes Cas9 protein. In a phase I, open-label trial, six patients with hATTR amyloidosis and polyneuropathy received a single dose of NTLA-2001 with a total RNA dose of either 0.1 mg/kg or 0.3 mg/kg. After day 28, the mean reduction in serum TTR protein from baseline was 52 percent in the 0.1 mg/kg group and 87 percent in the 0.3 mg/kg group. (Table) [N Engl J Med 2021;385:493-502]

Vaccines against flu, RSV

“In the post–COVID-19 era, we continue to develop vaccines against various viruses, including influenza virus and respiratory syncytial virus [RSV],” Karikó said.

Among mRNA-based seasonal influenza vaccine candidates, mRNA-1010 encoding haemagglutinin (HA) of four influenza virus strains, namely, H1N1, H3N2, B-Victoria, and B-Yamagata, was assessed in a three-part, randomized, phase I/II trial. Results from part 1, a placebo-controlled segment involving healthy adults aged ≥18 years, showed that mRNA-1010 (50 μg, 100 μg, or 200 μg) induced HA inhibition (HAI) titres against all vaccine-matched strains. In part 2, medically stable participants ≥18 years of age received either mRNA-1010 (50 μg, 100 μg, or 200 μg) or the standard-dose, quadrivalent inactivated vaccine. Participants given mRNA-1010 produced higher HAI titres for influenza A strains vs those who received the inactivated vaccine, with similar HAI titres reported for influenza B strains between the two groups. (Table) [Nat Commun 2023;14:3631]

mRNA-1345 is an RSV vaccine encoding the prefusion-stabilized F glycoprotein in RSV. In a phase I, placebo-controlled trial involving 74 younger adults (age, 18–49 years) and 202 older adults (age, 65–79 years), mRNA-1345 (50 μg, 100 μg, or 200 μg) significantly boosted antibody titres at 1 month and maintained a minimal dose response for 6 months, with similar immunogenicity between the age groups. (Table) [Open Forum Infect Dis 2022;9(Suppl 2):ofac492.312]

Safety considerations

When discussing the safety of mRNA-based vaccines, Karikó said that injection-site reactions are the most frequent local adverse events (AEs) in clinical trials. [Exp Mol Med 2023;55:1305-1313; Lancet 2017;390:1511-1520; Nat Commun 2023;14:3631; Open Forum Infect Dis 2022;9(Suppl 2):ofac492.312]

“Adjuvants [eg, LNP] may contribute to [certain] AEs by inducing immune responses. However, in vitro transcribed [IVT] mRNA undergoes degradation via physiological pathways, [reducing the risk of metabolite toxicity,]” Karikó explained. [Exp Mol Med 2023;55:1305-1313; Nat Rev Drug Discov 2018;17:261-279]

Future prospects

Preclinical and early-phase studies indicate many potential applications of mRNA technology, including pancreatic cancer, sickle-cell anaemia, methylmalonic acidaemia, as well as allergies to peanut and dust mites. [Nature 2023;618:144-150; Science 2023;381:436-443; EBioMedicine 2019;45:519-528; ACS Nano 2023;17:4942-4957; Allergy 2022;78:315-318]

“Notably, this technology allows in vivo protein expression, which provides advantages in protein replacement therapy over complex production processes necessary for therapeutic proteins, such as insulin, enzymes and growth hormones,” Karikó suggested. [Nat Rev Drug Discov 2014;13:759-780; Front Bioeng Biotechnol 2021;9:717326]

“We are working on an advanced system to enhance intracellular delivery of LNP-encapsulated mRNA,” she shared. “To minimize the potential risk of AEs, we are optimizing the mRNA platform to achieve elevated protein levels in vivo at lower mRNA doses.”