ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade

Abstract

Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27. ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days. In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539).

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“… 140 Humanized IgG1     AK002Sialic acid immunoglobulin-like lectins 8 (Siglec-8)afucosylatedFUT8 –/– CHO cells (Potelligent® Technology)Information not available Humanized IgG1     BMS-986218T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Information not available Human IgG1 (f)      Cusatuzumab/ARGX-110Humanized IgG1CD70, a member of TNF receptor ligand familyafucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Fucosylated version shown potent tumor growth inhibition in Raji xenograft mice (g) Silence et al. 141       DS-5573aB7-H3, a member of B7 familyafucosylatedFUT8 −/− CHO cells (Potelligent® Technology)DS-5573a showed dose dependent and significant tumor inhibition in MDA-MB-231-bearing SCID miceNagase-Zembutsu et al. 142 Humanized IgG1     Gatipotuzumab/ PankoMab-GEX/ GT-MAB 2.5 GEXTumor specific glycoepitope of Muc1 (TA-Muc1)ReducedHuman glycoengineered production cell lines (GlycoExpress technology)Information not available Humanized IgG1     …”

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform

“…The two antibodies were isolated from antibody libraries made from actively immunized Lama glama with either human CD70 or MET over-expressing cells using phage display. 27,28 Both CD70 (a membrane-bound cytokine) and MET (a tyrosine kinase receptor) play important roles in tumor growth/survival, angiogenesis and metastasis. 29,30 Our acquired candidate llama-derived antibodies were subjected to structure determination by X-ray crystallography.…”

“…For example, a diverse set of camelid antibodies directed against a range of epitopes on human interleukin (IL)-6, IL-1b, CD70 and MET was selected from phage libraries of antibodies synthesized from immunized animals (data not shown). 27,28 To reveal how foreign human therapeutic target proteins are in sequence compared to their camelid counterparts, an alignment was performed focusing on the above-mentioned human antigens (including IL-1a and tumor necrosis factor) using the sequences of camelid orthologs retrieved from WGS genomic databases ( Table 3). As a reference, sequences of the macaque orthologs were also included, because they are known to have a close phylogenetic relationship to humans.…”

CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies

“…68,69 In addition, due to the very limited expression on activated lymphocytes and on some tumor cells, strategies to target CD70 expressing cells with immunoconjugates or antibodies with enhanced antibody-dependent cellular cytotoxicity are exploited. 31,57 We recently documented that CD27…”