Juan Carlos Lopez

Andy Marshall

Lipid nanoparticles (LNPs), like those used in the FDA-approved siRNA drug Onpattro, remain the delivery vehicle of choice for mRNAs, gene-editing and base-editing therapies. One drawback of intravenously administered LNPs is adsorption of apolipoprotein E triggers rapid liver uptake via low-density lipoprotein (LDL) and other receptors on hepatocytes. This results in a relatively short half-life and limit application of LNPs in other organs. Peter Cullis, from the University of British Columbia, and his team report in Nature Communications a new LNP design that promises to enhance their lifetime in the blood.

In previous work, the team had established that LNPs consisting of an oil droplet of ionizable lipid like MC3, surrounded by a monolayer of bilayer-forming lipids like egg sphingomyelin and cholesterol, further surrounded by a proper lipid bilayer lasted longer in the circulation. In their new study, they systematically modified the ratio of bilayer lipid to ionizable lipid (R_B/I) and found that LNPs with R_B/I=4 showed liposomal morphology, high mRNA encapsulation efficiency, and excellent transfection properties in vitro and in vivo. Moreover, these LNPs with high proportions of bilayer forming lipids lasted longer in the circulation and showed higher transfection efficacy in lymph nodes and pancreas than Onpattro-like LNPs.

Cullis and his colleagues propose that the prolonged blood circulation lifetime is attributed to reduced plasma protein adsorption. The transfection competency of liposomal LNP systems is attributed to export of the solid core containing mRNA from the LNP as the endosomal pH is lowered. Their transfection potency, in turn, appears to depend on the cytoplasmic release of complexes that include mRNA and ionizable lipid, complexes that are generated as the endosome matures and its pH decreases. This work represents a promising strategy to increase the therapeutic index of drugs delivered by LNPs.

The new LNPs are being developed by Nanovation Therapeutics, a preclinical startup co-founded by Cullis in 2021. In September, Nanovation clinched a $600 million deal with Novo Nordisk to license worldwide rights to its long-circulating LNPs for extra hepatic delivery of two base-editing therapies for rare genetic diseases, and up to five additional targets in cardiometabolic and rare diseases. Cullis is a serial entrepreneur who has founded several companies around lipid-based delivery systems for nucleic acid-based drugs, including Inex Therapeutics/Protiva Biotherapeutics/Tekmira/Arbutus Pharma and subsequently Acuitas Therapeutics, which developed the MC3 LNP for Onpattro in collaboration with Alnylam Pharmaceuticals. The group also collaborated with Drew Weissman of the University of Pennsylvania on LNPs for mRNA vaccines, which lead to their use in mRNA COVID-19 vaccines.

To be a broad platform for the liver and beyond, LNPs must compete with several other delivery modalities, such as viral vectors and conjugates. In liver delivery, triantennary GalNAc-conjugated siRNAs, which target asialoglycoprotein receptors on hepatocytes, are now the delivery vehicle of choice for liver-targeted siRNAs. Apart from circulation lifetime, another issue that LNPs must contend with is organ accessibility due to fenestrations in blood vessels. In the case of the liver, pancreas, and bone marrow, pores are greater than 60 nm, allowing LNPs access to tissue. For mRNA vaccines, blood filtering lymph nodes also represent an excellent LNP target. However, tissues, such as brain (with its accompanying blood brain barrier), muscle and kidney have much tighter fenestrations (<15 nm), presenting an uphill delivery challenge for intravenous LNPs.

Juan Carlos Lopez

Andy Marshall

A growing stable of biopharma companies are developing biparatopic antibodies, which hit the same target via two non-overlapping epitopes. Compared with monospecific mAbs, such antibodies display enhanced binding through increased avidity, slower target dissociation, improved internalization, and greater specificity against drug target families where members share significant structural similarity. Now in the Journal of Clinical Investigation, a group at the Broad led by William Sellers describes biparatopic mAbs that inhibit fibroblast growth factor receptor 2 fusions, which are found in a variety of cancers, including intrahepatic cholangiocarcinomas (ICCs).

Sellers and his team showed that their mAbs inhibit signaling through FGFR2 fusions and inhibit ICC proliferation. They generated a panel of 15 biparatopic antibodies from 6 parental human antibodies and systematically tested them for their anti-proliferative activity on cells expressing FGFR2 fusions. Two showed greater potency than the parental antibodies, both in vitro and in vivo. Moreover, these biparatopic antibodies potentiated the action of FGFR2 inhibitors on cancer cells, and their inhibitory effect persisted, even against FGFR2 fusions with mutations that drive drug resistance. Mechanistically, the biparatopic antibodies promoted internalization and lysosomal degradation of FGFR2 fusions.

Sellers is also a scientific founder of Cambridge, Mass-based RedRidge Bio, which was funded in March via an undisclosed Series A venture round. Another recent startup, Attovia, took its first VHH biparatopic nanobody program against IL-31 into the clinic earlier this year and is collaborating with SciNeuro Pharmaceuticals on a neurology target.

The FGFR2 fusion work follows in the footsteps of studies by Regeneron demonstrating that biparatopic antibodies are effective inhibitors of oncogenic fusions of other receptor tyrosine kinases (RTKs). In that work, Regeneron researchers targeted fusions of another FGFR family member, FGFR3. In theory, the approach should be generalizable to any cancer arising from RTK fusions.

Biparatopic antibodies can work either in cis (binding the same target twice) or trans (binding two different molecules of the same target; e.g., to facilitate receptor clustering). Although they have been in clinical testing since 2011, it took until 2022 for the first biparatopic product to reach the market. Nanjing, China-based Legend Biotech (now J&J) got FDA approval for a T-cell therapy against refractory multiple myeloma featuring a chimeric antigen receptor (CAR) based on two single-domain antibodies targeting two different epitopes on B-cell maturation antigen (BCMA). Last November, FDA also gave the green light to Jazz Pharmaceuticals and Zymeworks’s zanidatamab, a biparatopic mAb that binds HER2 in trans and is indicated for patients with HER2-positive biliary tract cancer.

Similar to the antibody drug conjugate (ADC) space, a commercial stampede is currently underway in China to develop biparatopic mAbs against HER2, with at least 4 companies (Xuanzhu Biopharm, Alphamab Oncology, Chia Tai Tianqing Pharmaceutical and Beijing Mabworks) with products in clinical development. Given that big pharma has yet to make major announcements around biparatopic mAbs—notwithstanding AstraZeneca’s/Medimmune’s discontinued effort to develop MEDI4276, an anti HER2 ADC based on a biparatopic scaffold— the recent co-development partnership deal between Pierre Fabre Laboratorie and RedRidge Bio likely augurs more deal activity around this antibody modality in the near future.