Abstract
BackgroundThe CTLA-4 blocking antibody ipilimumab has demonstrated substantial and durable effects in patients with melanoma. While CTLA-4 therapy, both as monotherapy and in combination with PD-1 targeting therapies, has great potential in many indications, the toxicities of the current treatment regimens may limit their use. Thus, there is a medical need for new CTLA-4 targeting therapies with improved benefit-risk profile.MethodsATOR-1015 is a human CTLA-4 x OX40 targeting IgG1 bispecific antibody generated by linking an optimized version of the Ig-like V-type domain of human CD86, a natural CTLA-4 ligand, to an agonistic OX40 antibody. In vitro evaluation of T-cell activation and T regulatory cell (Treg) depletion was performed using purified cells from healthy human donors or cell lines. In vivo anti-tumor responses were studied using human OX40 transgenic (knock-in) mice with established syngeneic tumors. Tumors and spleens from treated mice were analyzed for CD8+ T cell and Treg frequencies, T-cell activation markers and tumor localization using flow cytometry.ResultsATOR-1015 induces T-cell activation and Treg depletion in vitro. Treatment with ATOR-1015 reduces tumor growth and improves survival in several syngeneic tumor models, including bladder, colon and pancreas cancer models. It is further demonstrated that ATOR-1015 induces tumor-specific and long-term immunological memory and enhances the response to PD-1 inhibition. Moreover, ATOR-1015 localizes to the tumor area where it reduces the frequency of Tregs and increases the number and activation of CD8+ T cells.ConclusionsBy targeting CTLA-4 and OX40 simultaneously, ATOR-1015 is directed to the tumor area where it induces enhanced immune activation, and thus has the potential to be a next generation CTLA-4 targeting therapy with improved clinical efficacy and reduced toxicity. ATOR-1015 is also expected to act synergistically with anti-PD-1/PD-L1 therapy. The pre-clinical data support clinical development of ATOR-1015, and a first-in-human trial has started (NCT03782467).
Highlights
The CTLA-4 blocking antibody ipilimumab has demonstrated substantial and durable effects in patients with melanoma
ATOR-1015 completely blocked CD80 and CD86 from binding to CTLA-4 expressed by Chinese hamster ovary (CHO) cells (Additional file 2: Figure S1B)
ATOR-1015 activates T cells in the tumor where target expression and density of Fcγ receptor-expressing cells are high, but not in the spleen. This is in line with previous studies showing that most agonistic Tumor necrosis family receptor (TNFR) antibodies depend on crosslinking for induction of receptor superclustering to achieve a good agonistic effect [23, 27, 28], and that CTLA-4-mediated T-cell signaling and function is improved upon Fc-FcγR engagement [29]
Summary
The CTLA-4 blocking antibody ipilimumab has demonstrated substantial and durable effects in patients with melanoma. The approval of the anti-CTLA-4 antibody ipilimumab (Yervoy®) in 2011 revolutionized the immuno-oncology (IO) field by significantly improving long-term survival in patients with metastatic melanoma. Six additional checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have been approved, and a large number of other IO drugs have entered clinical development. CTLA-4 is constitutively expressed on T regulatory cells (Tregs) and is upregulated on other T cells upon activation [4, 5]. Several mechanisms of action of CTLA-4 blocking antibodies have been proposed, including activation of effector T cells by blocking the CTLA-4 pathway and depletion of Tregs via antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) [6, 8,9,10,11]. The relative clinical importance of these mechanisms is still debated [8, 12, 13]
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