Abstract 5552: BT7480, a novel fully synthetic tumor-targeted immune cell agonist (TICATM) induces tumor localized 4-1BB agonism

Abstract

Costimulatory molecules expressed on activated T and NK cells such as 4-1BB (CD137/TNFRSF9) can be leveraged for cancer immunotherapy. Despite compelling preclinical data, 4-1BB agonistic antibodies have been hampered by failure to delineate hepatoxicity from efficacy in the clinic [1,2]. Next generation strategies are focused on bispecific approaches aimed at promoting target-mediated clustering of 4-1BB to limit systemic and liver effects [3,4]. Bicycles® are fully synthetic, constrained bicyclic peptides that have antibody-like affinity and selectivity to their targets. Unlike traditional biologic approaches, the small size (~2 kDa) and tunable pharmacokinetic (PK) parameters of Bicycles enable superior tumor penetration and allow exploration into the relationship between pulsatile dosing and 4-1BB activation while de-risking hepatoxicity concerns due to a differentiated renal elimination mechanism combined with a tumor-localized immune response. We hypothesized that clustering and activation of 4-1BB could be achieved by conjugating a 4-1BB binding Bicycle to a tumor antigen targeting Bicycle. BT7480 is a tumor-targeted immune cell agonist (TICATM) targeting Nectin-4 and agonizing 4-1BB. Nectin-4 (PVRL4) is highly expressed on numerous tumors with unmet medical need, including bladder, pancreatic, breast, ovarian, esophageal, and lung. BT7480 exhibits highly potent 4-1BB agonism in an engineered 4-1BB reporter system that correlates with Nectin-4 surface expression on the co-cultured tumor cells. In addition, BT7480 induces robust production of interleukin-2 (IL-2) and interferon gamma (IFNγ) in primary PBMC/tumor cell co-culture assays. This activity is strictly dependent on the tumor cells expressing Nectin-4 and on the ability of the TICA to bind to both Nectin-4 and 4-1BB. Nectin-4/4-1BB TICAs are also target-specific immune cell stimulators of patient-derived lung tumors with an intact immune microenvironment. Intermittent dosing of BT7480 led to robust anti-tumor efficacy with 22 out of 24 complete responders (CRs) in a MC38 (Nectin-4-expressing) syngeneic mouse model. Importantly, a memory response was established as the CR mice were resistant to re-challenge with MC38 tumors. Additionally, BT7480 led to increased intratumoral T cell infiltration without elevation of liver enzymes in a CT26 (Nectin-4-expressing) syngeneic mouse model. In non-human primates (NHPs), BT7480 exhibits dose linear exposure and is well tolerated up to 10mpk. Further dose-range finding and safety analysis in NHPs is currently ongoing. BT7480 represents a new generation of chemically synthetic tumor antigen targeted 4-1BB agonists. References 1. Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017;23(8):1929-1936. 2. Chester et al. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood 2018;131(1): 49-57. 3. Hinner et al. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. Clin Cancer Res. 2019; 25(19): 5878-5889. 4. Claus C, Ferrara, C, Xu W, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019; 11(496): eaav5989. Citation Format: Kristen Hurov, Punit Upadhyaya, Johanna Lahdenranta, Jessica Kublin, Jun Ma, Elizabeth Repash, Marianna Kleyman, Julia Kristensson, Liuhong Chen, Eric Haines, Sailaja Battula, Kevin McDonnell, Nicholas Keen. BT7480, a novel fully synthetic tumor-targeted immune cell agonist (TICATM) induces tumor localized 4-1BB agonism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5552.

Diverse drug delivery systems for the enhancement of cancer immunotherapy: an overview

“…What is more prominent in this aspect is the PDCs from Bicycle Therapeutics. Based on a fully synthetic restricted bicyclic peptide technology, Bicycle Therapeutics has developed a novel peptide coupling as a tumor-targeted immune cell agonist ™ (BicycleTICA ™ ) (177). They link peptides targeting CD137 and tumor-specific receptors, respectively, via a three-armed branched polyethene glycol junction.…”

Therapeutic prospects of nectin-4 in cancer: applications and value

“…Transcriptional analysis has shown that Nectin-4 and CD137 are co-expressed in a variety of cancers. BT7480 targets Nectin-4-expressing tumor cells and then binds to and agonizes CD137 on nearby immune cells to remodel the tumor immune microenvironment, thereby eliminating tumor cells and inhibiting tumor recurrence (115,116). Compared with CD137 activation alone, immune killing after targeted activation shows a better therapeutic effect and less liver toxicity.…”

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

“… 20 , 81 Other molecules (DSP107, BT7480) do not display such PK-improving properties, and, at least for BT7480, a reduced half-life has been reported. 82 …”