Earlier this month the World Health Organisation (WHO) released Proposed International Nonproprietary Name List 125 (PL125), comprising the therapeutics entering clinical trials during the first half of 2021. We have just added this data to our Therapeutic Structural Antibody Database (Thera-SAbDab), bringing the total number of therapeutic antibodies recognised by the WHO to 711.
This is up from 651 at the end of 2020, a year which saw 89 new therapeutic antibodies introduced to the clinic. This rise of 60 in just the first half of 2021 bodes well for a record-breaking year of therapeutics entering trials.
The latest clinically-investigated molecules extend many of the trends seen in the industry over recent years. Bispecifics continue their inexorable rise, making up 11 of the 60 new entries (+19.6% the number of bispecifics recorded at the end of 2020, more than double the growth of the overall database [+9.2%]). Indeed, the diversity of antibody formats in this update is the greatest yet: monoclonal whole mAbs, monoclonal mAb fusion proteins, scFv-IGHC, bispecific whole mAbs, bispecific scFv-scFv-scFc, bispecific scFv-CH2-CH3-scFv, bispecific mixed mAb and Fab, bispecific mixed single chain VH-VH-CH2-CH3 and bispecific nanobody VHH-CH2-CH3 dimer. We should soon have a meaningful number of datapoints to establish whether antibodies based on non-native formats can exhibit good therapeutic profiles in vivo.
One slight surprise in this update was the relative lack of nanobody-based therapeutics (+1, now 6 in total), given the current hype surrounding nanobodies within the broader research community. My guess is that this reflects an inevitable lag while companies develop and improve their own in-house scaled-up nanobody expression/formulation/assay pipelines, and that it is only a matter of time before we see this number rise significantly.
The number of molecules in the clinic against the SARS-CoV-2 spike protein has doubled to 16 (+8) since the turn of the year. According to metadata and cross referencing with CoV-AbDab, 15 specifically target the receptor binding domain, while the epitope of one, Adintrevimab, is still unclear.
However, the headline result of this update must be the number of new antigens targeted by therapeutics. Traditionally, the industry has “played it safe” in terms of antigens, going after a common set of targets whose role in disease has been extensively studied. This time around, however, 14/60 (23.3%) of therapeutics bind to at least one antigen that has never been targeted by a therapeutic before. These are:
CLU (clusterin): Sotevtamab
CSF3R (colony stimulating factor 3 receptor): Anumigilimab
DKK1 (dickkopf WNT signaling pathway inhibitor 1): Sirexatamab
GREM1 (gremlin 1 DAN family BMP antagonist): Ginisortamab
HTRA1 (HtrA serine peptidase 1): Galegenimab
IL13RA1 (interleukin 13 receptor subunit alpha): Eblasakimab
KIT (KIT protooncogene receptor tyrosine kinase): Barzolvolimab
Light Chain Amyloid Fibrils: Amselamimab
LRRC32 (Leucine rich repeat containing 32): Livmoniplimab
MUC17 (mucin-17): Vepsitamab
PAUF (pancreatic adenocarcinoma up-regulated factor): Ulenistamab
TfR1 (human transferrin receptor): Lupunafusp
TGFBR2 (transforming growth factor beta receptor type I): Dalutrafusp
TNFSF14 (tumor necrosis factor (TNF) superfamily member 1): Quisovalimab
Alongside an increasing number of experimental formats, this likely reflects the fact that increased efficiencies in therapeutic antibody development, for which we have continually strived as a community, are starting to bear fruit. With lesser-studied targets comes greater financial risk, which must surely have been mitigated through reduced early-stage developmental costs making them more economically viable to explore. Alongside this risk though comes great potential for field-changing reward; genuinely novel and transformative medications for patients. Let’s hope this trend of exploration continues long into the future, because we should all benefit as a result!
