The recent biOasis/MedImmune publication really highighted the superiority of the melanotransferrin (MTfR) receptor approach (via xB3 peptide aka Mtfp, as well as full length MTf) relative to the antibody-mediated transferrin receptor (TfR) approach. Medimmune had previously published (cited in this previous post) a similarly designed study using the anti-TfR approach. The conclusion in this recent biOasis/MedImmune paper that the xB3/MTfR approach is superior to the TfR approach in a nearly side by side comparison by an independent group speaks volumes. As Mark Day pointed out recently, many companies are still pursuing the TfR approach. But there are signs that these companies may be moving on from TfR strategies to other approaches and realizing that the compeitition (i.e. biOasis and xB3 for MTfR)) are using a superior approach. 

Back at the end of May (coincidentally the day after the biOasis/MedImmune publication) Denali completed a deal to buy F-star Gamma for their engineered Fc-antibody (Fcab) technology. Denali and F-star had a previous arrangement, which gave Denali their current TfR targeted Fcab that Denali is currently using as their antibody/enzyme transport vehicle. It sounds like this recently completed deal expands their work to cover two new, undisclosed transporter targets. Perhaps Denali is realizing that their TfR approach is inferior to other competing technologies (i.e. xB3 and biOasis) and are preparing to move on to another receptor. Perhaps a melanotransferrin receptor such as LRP1 is on Denali’s list?

Also of interest from the recent biOasis MD&A was an update on the recently concluded CQDM and Brain Canada collaboration that assessed single domain human antibody libraries at the NRC for their ability to cross the BBB and act as transport vectors. Two promising candidates emerged that have been selected for their BBB transport capability and efficacy in pharmacodynamic models. These will be added to the xB3 peptide vector family along with related IP, allowing the Company to pursue global commercialization of them, if warranted.

Mark Day recently mentioned Ossianix as a company still working on TfR single domain antibodies. https://www.ossianix.co.uk/. TfR approaches are known to be inferior to MTfR approaches as described above. Surely, the BBB crossing efficiency of xB3 was a good meter stick for determing the promise of the single domain antibodies that came out of the biOasis/CQDM/Brains Canada collaboration. Therefore, it is likely that these biOasis/CQDM/Brains Canada single domain antibodies are far superior to these Ossianix TfR targeted single domain antibodies. I wonder what receptor or target these two promising single domain antibodies are targeting? Could biOasis have something even better than xB3 up their sleeve?

One advantage of peptide ligand approaches, such as xB3, as opposed to an antibody approach that targets a specific receptor, is that a peptide ligand can potentially bind to multiple receptors whereas an antibody approach more likely targets only one receptor. Of course, some ligands might also be very specific for a single receptor. My point is that there could be both strengths and weaknesses to a peptide approach that binds to multiple receptors. 

While xB3 works through the LRP1 receptor according to biOasis, are there any published studies out there yet from biOasis that evaluate the specificity of xB3 for the LRP1 receptor? Could a explanation for the strength of xB3 relative to other competing technologies be that xB3 engages receptors other than LRP1 that augment its BBB transport capability? Reference 21 in the recent biOasis/MedImmune publication is cited as describing the identification of the 12 amino acid Mtf-pep. Looks like another paper should be published soon. Reference 21 is:  "Eyford BA, Abraham T, Munro L, et al. A peptide vector delivers siRNA across the blood-brain barrier resulting in attenuation of ischemic stroke. In revision. Nature Biomed Eng." Perhaps this paper will show some data evaluating the LRP1 specificity of xB3.

Lastly, Mark Day mentioned in a recent post another competitor Vect-Horus, using a peptide approach that targets the LDL receptor. According to Mark Day, xB3 from biOasis is far superior to this Vect-Horus approach. I'm still trying to read up on Vect-Horus and their published studies so that I can come to that same conclusion. But it is often difficult to compare studies to one another if the two studies are not well matched. According to Mark, biOasis achieves 10X brain/plasma ratio as Vect-Horus. However, I'm not sure which biOasis study or publication that Mark is using for comparison. It is often difficult to directly compare two studies if they are not well matched. Regardless, I do agree with Mark's criticim of Vect-Horus' peptide being LDL receptor specific. As shown in Figure 9 of this publication, there was still significant tissue uptake in LDL receptor knockout mice. Figure 9 showns ~2% tissue/plasma ratio in cortex of control mice and ~1% in LDL receptor knockout mice. I'll try to do some more digging on Vect-Horus and do another post at a later date.

Happy Canada Day and Independence Day to all!

BearDownAZ