No 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 purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels ( = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected. Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies. This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. .

(2014) A novel llama antibody targeting Fn14 exhibits anti-metastatic activity in vivo, mAbs, 6:1, 297-308,

Outcomes in elderly patients with acute myeloid leukemia (AML) are still adverse, as the majority does not qualify for intensive therapy or allogenic stem cell transplantation (ASCT). DNA hypomethylating agents (HMAs) induce remissions and prolong survival in a fraction of these patients. However, overall prognosis remains dismal and all patients progress due to therapy-resistant leukemia stem cells (LSCs). We recently demonstrated that HMAs upregulate the expression of CD70 on primary human AML LSCs, potentially contributing to HMA resistance and that blocking the cell-autonomous CD70/CD27 signaling inhibits proliferation and myeloid differentiation of LSCs and contributes to HMA resistance. Consequently, combining HMA treatment with a blocking αCD70 monoclonal antibody potently reduced colony formation of AML LSCs in vitro and effectively eliminated human AML LCSs in xenograft experiments. Based on these results, we initiated an open-label, non-controlled, non-randomized Phase 1/2 trial combining the HMA azacitidine (AZA) with ARGX-110, a human monoclonal antibody targeting CD70, in newly diagnosed AML patients unfit for intensive chemotherapy (ARGX-110-1601, NCT03030612). Trial design ARGX-110 with optimized antibody-dependent cell-mediated cytotoxicity (ADCC), is administered intravenously at 1, 3, 10 or 20 mg/kg once every two weeks (Q2W), in combination with a standard dose of AZA (75 mg/m² subcutaneously for 7 days every 28 days). A 2-week lead-in of ARGX-110 enables studying the effect of αCD70 antibody monotherapy. Primary objectives in the Phase 1 include determining the maximum tolerated dose of ARGX-110 in combination with AZA and the recommended phase 2 dose (RP2D). Secondary objectives comprise safety, pharmacokinetics and anti-leukemic activity of ARGX-110 alone or in combination with AZA (including overall response rate (ORR), frequencies of LSCs and minimal/measurable residual disease (MRD)). Results The trial is ongoing and as of 16th July 2018, 12 newly diagnosed AML patients were treated in the dose-escalation part of the trial, the results of which will be further updated in December 2018. The median age over the dose cohorts was 75 years (range 64-84) and included intermediate (N=6) and adverse (N=6) ELN risk groups. WHO subtypes were AML with recurrent genetic abnormalities (N=2), MDS-related changes (N=6), AML-NOS (N=3) and therapy-related myeloid neoplasms (N=1). No dose-limiting toxicity was observed and the combination of ARGX-110 with a standard dose of AZA was well tolerated. Hematological toxicities, in line with expected AZA toxicities, were the most frequently reported adverse events (AEs). At the cut-off, the ORR (complete remission [CR] + incomplete recovery [CRi] + partial remission [PR] + morphologic leukemia-free status [MLFS]) was 92% (11/12 patients); among the 11 evaluable subjects, the best response was CR/CRi for 9 patients (82%), 1 patient (9%) reached MLFS, and 1 (9%) PR, with 7 patients still on the trial (median duration on the trial at cut-off was 6.9 months [range: 2-14.4 months]). Significantly, 1 patient reached CR and was discontinued after 5 months to undergo ASCT. Five evaluable patients (45%) achieved MRD negativity by flow cytometry. Molecular MRD negativity was achieved in 3/8 patients with available results, two correlating with flow-MRD negativity. The mean time to response for the first 9 patients was 2.8 months and 3.4 months to reach best response. The 3 patients in the 20 mg/kg cohort did not all reach response at the time of cut-off. Based on pharmacokinetics, safety, and pharmacodynamic data, the RP2D of 10 mg/kg was established. Translational studies assessing LSC frequencies in bone marrow aspirates by limiting dilution colony assays and xenograft experiments revealed that ARGX-110 monotherapy and in combination with AZA significantly reduced LSC frequencies in AML patients. Conclusions ARGX-110 in combination with AZA is well tolerated and leads to a higher ORR compared to historical data for AZA alone. Clinical activity of the combination is observed in different AML subtypes and risk categories. Preliminary data indicate that ARGX-110 alone, and in combination with AZA, efficiently eliminates LSCs. These observations warrant further accelerated investigation of ARGX-110 in combination with AZA in AML patients unfit for intensive therapy. Disclosures Ochsenbein: argenx: Research Funding. Riether:argenx: Research Funding. Bacher:argenx: Research Funding. Höpner:argenx: Research Funding. Hinterbrandner:argenx: Research Funding. Van Rompaey:argenx: Employment. Moshir:argenx: Employment. Delahaye:argenx: Employment. Gandini:argenx: Employment. Erzeel:argenx: Employment. Hultberg:argenx: Employment. Fung:argenx: Consultancy. De Haard:argenx: Employment. Leupin:argenx: Employment.