TDCs represent a unique and potentially disruptive new class of drug conjugate therapeutics. Our initial focus is on the treatment of intractable cancers where we believe we can radically improve Therapeutic Index.
Our current development focus is the Folate Receptor alpha (FRα) program, a fast follower development project against a clinically validated target, where we believe we can make meaningful improvements in Therapeutic Index compared to contemporary approaches. FRα is a membrane bound folate binding receptor protein which has restricted expression in normal cells but is highly expressed in various tumors – most notably in ovarian and lung cancers, but also in endometrial, breast, certain forms of kidney cancer and cancer of the cervix. The density of FRα on tumor cells appears to increase with progressing disease making it an attractive therapeutic target for advanced stage cancers.
FRα is known to undergo significant recycling after internalization, making it a good choice for our SiLinker TDCs which can be designed to cleave in the early endosome (before a cell commits to recycling a proportion of internalized receptor-ligand complexes), as well as the lysosomal compartment where contemporary linker systems more typically release payload. We believe that FRα TDCs with triple payload cassettes can provide superior efficacy by rapidly delivering higher amounts of payload. At the same time, the rapid systemic clearance of the TDC, coupled with the use of Conditionally Active Payloads (CAPs), can reduce toxicity.
In late stage disease expression of FRα can vary widely, both between individual lesions in metastatic disease, and within a single lesion. The preferential use of CAPs in our TDCs – combined with the pH sensitive nature of our SiLinkers – could provide us with an additional competitive advantage in this setting by selectively releasing payload into the acidic (necrotic) tumor microenvironment for an improved tumor cell kill (which we refer to as an enhanced bystander effect).
We believe this approach offers us the opportunity to advance a highly differentiated clinical candidate with an improved Therapeutic Index into clinical trials.
FRα TDCs are efficacious in vivo
Our prototype FRα TDCs have validated the SiLinker and Payload Cassette components of our technology platform by demonstrating both efficacy and tolerability in in vivo mouse xenograft models.
We compared the in vivo activity of two prototype TDCs BB-01 and BB-03 in nude mouse xenograft models. BB-01, a TDC with a folic acid ligand coupled to a single Vinblastine silanol payload via a SiLinker, showed a clear dose response. The higher dose (5 μmol/kg three times a week for 2 weeks) showed cures in 3 out of 5 mice after 45 days in this study. At the lower dose of 3 μmol/kg (three times a week for 2 weeks) BB-01 was able to inhibit the growth of tumors but did not reduce the size of tumors or produce cures. In comparison, BB-03, a TDC with a folic acid ligand coupled to three Vinblastine silanol payloads in a payload cassette, was able to produce cures in the mice at 1 μmol/kg (three times a week for 2 weeks). This demonstrates the superior efficacy that can be obtained with payload cassette containing TDCs that deliver an equivalent amount of payload at lower doses than single payload containing TDCs.
We then made simple modifications to the spacer and adaptor elements in BB-03 to generate BB-11 and tested it in two different nude mouse xenograft models. In the KB model, where tumors express high levels of FRα, BB-11 demonstrated excellent activity at two different doses. BB-11 was able to provide cures with just two doses of 3 μmol/kg in the once-a-week dosing regimen. BB-11 was also efficacious in the OV90 model where tumors have only a moderate level of FRα.
All three TDCs, BB-01, BB-03 and BB-11, were well tolerated with no loss of body weight observed in the mice.
We are currently using our modular toolbox to further optimize our TDCs with the intent to nominate a candidate for IND enabling studies.