On January 20, 2022 Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, and BioInvent International AB ("BioInvent") (Nasdaq Stockholm: BINV), a biotech company focused on the discovery and development of novel and first-in-class immune-modulatory antibodies for cancer immunotherapy, jointly reported the publication of extensive preclinical proof-of-concept data for BT-001 in the Journal for ImmunoTherapy of Cancer (JITC) (Press release, Transgene, JAN 20, 2022, View Source [SID1234605652]). This peer-reviewed article demonstrates that their co-developed clinical stage product, based on Transgene’s patented oncolytic vector and encoding BioInvent’s proprietary anti-CTLA-4 antibody, has the potential to provide greater therapeutic benefit than systemically administered anti-CTLA-4 antibodies.
Systemically administered anti-CTLA-4 antibodies, such as the approved ipilimumab, have demonstrated substantial efficacy but also clinically-limiting toxicity.
The JITC paper provides in vivo evidence that vectorized anti-CTLA-4 antibodies delivered intratumorally (i.t.) can improve safety by reducing their systemic exposure. Efficacy may also be improved, with evidence from the immunocompetent murine model showing that vectorized anti-CTLA-4 antibodies have anti-tumoral activity even against ‘cold tumors’ that are resistant to systemically-delivered checkpoint inhibitors. Furthermore, the precise targeting of the antibody to a unique functional epitope of CTLA-4 provides a higher level of regulatory T cells (Treg) depletion than ipilimumab.
"This strong preclinical data supports the development of our oncolytic virus BT-001 as an effective agent to treat solid tumors. We have vectorized a uniquely targeted anti-CTLA-4 antibody for intratumoral delivery and shown in vivo evidence that this reduces systemic toxicity, addresses ‘cold tumors’ and provides excellent tumor-selective Treg depletion. We are keenly anticipating progress in our ongoing Phase 1/2a clinical study with BT-001," said Bjorn Frendéus, Chief Scientific Officer of BioInvent.
"These data demonstrate the relevance of the approach which is based on combining our respective technologies to fully exploit the synergy between oncolytic vector, targeted delivery of a potent payload targeting immunosuppressive cells, and recruitment of effector T cells. The antitumor properties showed in this JITC publication give us great confidence in the results we expect from the further clinical development of BT-001," added Éric Quéméneur, Executive VP & Chief Scientific Officer of Transgene.
The safety-relevant data, published in JITC, show that a murine vector version of BT-001 delivered sustained levels of CTLA-4-receptor-saturating antibodies within tumors but low, sub-saturating exposure in blood and the non-tumor tissue. These antibody levels were associated with high depletion of Tregs in the tumor but the absence of systemic Treg depletion, notably in the spleen.
The study also provides several key insights into likely mechanisms underlying the efficacy of BT-001. Vectorized anti-CTLA-4:
triggered both Fcγ-receptor-dependent Treg depletion and antigen cross-presentation, mechanisms known to trigger and promote long-lasting, systemic, CD8+ T cell antitumor immunity;
showed broad antitumor activity, including activity against murine ‘cold tumor’ models which are resistant to systemic checkpoint inhibitors;
showed additive or synergistic anti-tumor activity when combined with anti-PD-1.
The JITC paper is titled "Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors" and can be accessed here.
Recruitment in the ongoing Phase I/IIa clinical study of BT-001 (NCT04725331) in Europe is progressing steadily. The trial assesses BT-001 as a single agent and in combination with the PD-1 checkpoint inhibitor pembrolizumab against solid tumors. Initial Phase I data are expected in the first half of 2022.
BT-001 is an oncolytic virus generated using Transgene’s Invir.IO platform and its patented large-capacity VVcopTK-RR- oncolytic virus, which has been engineered to encode both a Treg-depleting human recombinant anti-CTLA-4 antibody generated by BioInvent’s proprietary n-CoDeR/F.I.R.S.T platforms, and the human GM-CSF cytokine. By selectively targeting the tumor microenvironment, BT-001 is expected to elicit a much stronger and more effective antitumoral response. As a consequence, by reducing systemic exposure, the safety and tolerability profile of the anti-CTLA-4 antibody will be greatly improved.
BT-001 is being co-developed as part of a 50/50 collaboration on oncolytic viruses between Transgene and BioInvent. To know more on BT-001, watch our video here.