BioInvent International has announced the presentation of promising new data on its anti-tumor necrosis factor receptor 2 (TNFR2) program at the American Association for Cancer Research (AACR) Annual Meeting.
The results shows that TNFR2 is particularly upregulated on tumor-associated regulatory T cells (Tregs) and has been shown to be important for their expansion and survival. As a part of its Treg program, BioInvent identified and characterized a wide panel of TNFR2-specific antibodies, generated from its n-CoDeR library and F.I.R.S.T discovery tool.
Two antibody variants with distinct molecular and functional properties have been selected for development for treatment of solid cancer based on careful characterization of their mechanisms of action: BI-1808, a ligand-blocking Treg depleting antibody, and BI-1910, a TNFR2 agonist. The two antibody candidates showed strikingly different FcγR-dependence for optimal antitumor activity and – while evoking different initial immune cell mediated events – both elicited transformation of the tumor immune landscape associated with powerful anti-tumor efficacy, states the company.
A compelling preclinical antitumor activity
Björn Frendéus, Chief Scientific Officer at BioInvent, explains more about the translational data package that will be presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II, taking place June 22-24 (abstract is posted online today May 15th).
“Data presented in the posters (two posters on two different programs ) show for the first time the compelling preclinical antitumor activity of our therapeutic anti-TNFR2 antibodies (BI-1808 and BI-1901) as well as of our Treg-depleting oncolytic virus (BT-001) – the latter co-developed with French vaccine experts Transgene. Antibodies and targets of both programs were identified and developed using BioInvent’s F.I.R.S.T platform screening for antibodies and targets with superior immune activating antitumor activity with human primary cancer patient’s cells and in animal models representing cancer patient immune phenotypes associated with response, incomplete response, or resistance to cancer immunotherapy,” says Frendéus.
The data show that BioInvent’s anti-TNFR2 mAbs can regress large inflamed tumors as single agent, and have activity and synergize with anti-PD-1 to induce cure in models poorly responsive or resistant to checkpoint blockade. Their anti-CTLA-4-encoding oncolytic virus similarly shows broad antitumor activity across a wide range of solid cancer and liquid tumors, with data supporting an improved therapeutic window of anti-CTLA-4 antibody treatment.
“Potentially therefore our anti-TNFR2 and anti-CTLA-4 programs, in addition to providing strong anti-tumor activity by themselves, may afford tolerable strategies for combining and enhancing on different clinically validated checkpoint blockers,” says Björn Frendéus, CSO, BioInvent.
Not only in cancer but also in autoimmune diseases
Frendéus also says that these findings may also be used in autoimmune diseases.
“There is an abundance of data indicating opposing roles of Treg and TNFR2 in cancer and inflammatory/autoimmune disorders. We are very excited and have just started exploring activity in models of inflammation. Again, our unique access to mechanistically distinct human lead and matching surrogate mAbs potentially provide a fast-track to expand into new indications. Through our eco-system of internationally leading Scientific Advisory Board members, collaborators and the BioInvent internal crew, which comprises several PhDs including myself that are trained in inflammation, we are in a good position to probe this possibility. Having said this, our absolute internal focus on discovering and developing targets and mAb for cancer immunotherapy remains. Potential utilities in inflammation represent an apparent upside that will be probed mainly through our cutting-edge collaborators,” he says.
TNFR2 for cancer immunotherapy
BioInvent expect to be the first company in the clinic with antibodies to TNFR2 for cancer immunotherapy.
“Based on our existing strong preclinical and translational package, which spans from mouse to non-human primate to human, and careful mechanistic dissection we are confident that we in BI-1808 will have not only a first-in-class but also best-in-class anti-TNFR2 antibody. With regard to our anti-CTLA-4 encoding oncolytic virus, our Treg-depleting antibody is clearly differentiated from clinically validated ipilimumab. Its incorporation into Transgene’s Vaccinia-based oncolytic virus vector, Vaccinia being a potent immune activator and perhaps the best studied virus in relation to human vaccine therapy, and our super strong preclinical data package suggest that we will have a best-in-class oncovirotherapy approach, which for the first time could enable safe co-administration of therapeutically optimal doses of anti-CTLA-4 with anti-PD-1,” says Frendéus.
“We are confident that we in BI-1808 will have not only a first-in-class but also best-in-class anti-TNFR2 antibody.”
Clinical trials this year
BioInvent is now progressing both BI-1808 and BT-001 forcefully toward the clinic and expect to enter clinical trials this year (2020).
The modes of action for the antibodies
All of these therapies i.e. BioInvent’s anti-TNFR2 mAbs, which comprise the ligand blocking depleting BI-1808 and the agonist BI-1910, and the anti-CTLA-4 encoding oncolytic virus combat cancer by activating immunity.
“Intriguingly, we have evidence suggesting that our two types of anti-TNFR2 mAb – despite binding to the same target –activate antitumor immunity via different mechanisms, at least initially. This indicates potentially different applications. BI-1808 uniquely shows strong ability to deplete intratumoral T reg cells. This is a good thing because Treg cells are amongst the most immune suppressive cells thought to promote cancer resistance to immunotherapy, and they are frequently found in tumors. Conversely, but equally intriguingly, both types of anti-TNFR2 mAbs expand intratumoral CD8+ T cells – one of the most powerful antitumor cells of the immune system and predictors of positive cancer outcome,” explains Frendéus.
Whilst he and his colleagues have just begun the journey of dissecting the molecular and cellular mechanisms underlying their single agent antitumor activities, and apparent synergistic activities with anti-PD-1, it is clear that TNFR2 represents a particularly powerful target for antibody-based cancer immunotherapy.
“Between our mechanistically distinct mAb and closely matched mouse surrogate antibodies, BioInvent is in a unique position to identify most appropriate use and biomarkers to guide clinical development–- both of monotherapy and combination treatments.
Our anti-CTLA-4 encoding oncolytic virus incorporates the mechanisms of two clinically approved immune modulators, imlygic and ipilimumab, with the edge of expected enhanced intratumoral Treg depletion and potential of improved tolerability. Pending translation to the clinic, our sum preclinical data indicate a safe way to simultaneously target the three clinically validated axes of anti-CTLA-4, anti-PD-1/PD-L1 and oncolytic virotherapy,” concludes Björn Frendéus.
Photo of Björn Frendéus: BioInvent