cusatuzumab (ARGX-110)

P2, N=120, Not yet recruiting, OncoVerity, Inc.

We recently documented that targeting CD70, the ligand of the tumor necrosis factor receptor (TNFR) CD27, by the antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced monoclonal antibody (mAb) cusatuzumab eliminates LSC...Our findings reveal that LIGHT/LTbR-signalling is crucial for the pathogenesis of AML and especially for the maintenance and expansion of LSCs. We developed and validated novel LIGHT targeting mAbs in vitro and in vivo for further development in clinical trials.

Moreover, anti-PD1 (nivolumab), anti-PDL1 (pembrolizumab, atezolizumab), anti-CD52 (alemtuzumab), anti-KIR3DL2-CD158k (lacutamab), and anti-CD70 (cusatuzumab) have been tested or are under investigations in phase II trials. In recent years, targeted (biological) therapies have become available also for primary cutaneous T-cell lymphomas (PCTCLs) including anti-CD30 (brentuximab vedotin) in mycosis fungoides, primary cutaneous anaplastic large T-cell lymphoma, lymphomatoid papulosis; anti-CCR4 (mogamulizumab) in Sezary syndrome; anti-CD123 (tagraxofusp) in blastic plasmocytoid cell neoplasm. The expression of these epitopes on neoplastic cells in skin biopsies or blood samples plays a central role in the management of PCTCL patients. This narrative review aims to provide readers with an update on the latest advances in the newest therapeutic options for PCTCLs.

Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887).

Moreover, different monoclonal antibodies (Abs) and Ab-derivates were tested including a CD70 blocking antibody (αCD70) and an antibody-dependent cell-mediated cytotoxicity (ADCC) optimized antibody (cusatuzumab, ArgenX) that activates FcγR-expressing effector cells to assess the therapeutic potential of targeting CD70 in MM... Our results indicate that CD70-expressing MM cells have a stem-cell like phenotype and propagate the disease. Targeting CD70 is a promising new therapy especially in advanced disease.

In vitro cell-based assays demonstrated that IMM40H had considerably stronger CD70-binding affinity than competitor anti-CD70 antibodies, including cusatuzumab, which enabled it to block the interaction of between CD70 and CD27 more effectively...A strong synergistic effect between IMM01 (SIRPα-Fc fusion protein) and IMM40H was recorded in Burkitt's lymphoma Raji and renal carcinoma cell A498 tumor models...IMM40H is a high-affinity humanized IgG1 specifically targeting the CD70 monoclonal antibody with enhanced Fc-dependent activities. IMM40H has a dual mechanism of action: inducing cytotoxicity against CD70+ tumor cells via various effector functions (ADCC, ADCP and CDC) and obstructs the proliferation and activation of Tregs by inhibiting CD70/CD27 signaling.

Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.

In this regard, different Abs and Ab-derivates were tested including a CD70 blocking antibody (αCD70) and an antibody-dependent cell-mediated cytotoxicity (ADCC) optimized antibody (cusatuzumab) that activates FcγR-expressing effector cells... Although the treatment options of MM have rapidly increased during the last years, MM remains an incurable disease that ultimately leads to death. Our results indicate that especially advanced MM stages express high levels of CD70. In addition, our results indicate that CD70/CD27 cell-autonomous signaling contributes to disease progression and therapy resistance and identifies CD70 as potential target in MM.

These CAR constructs include 4 VHH sequences and a human scFv containing VH and VL derived from cusatuzumab... Our results indicate a promising VHH-based CD70 CAR-T cells for RCC therapy, supporting further development for future clinical trial and application.

Notably, in a U266 multiple myeloma model, IMM40H, at the dose of 0.3 mg/kg, completely inhibited tumor growth in a way that therapeutic effects appeared significantly earlier than that of cusatuzumab at a higher dose of 1 mg/kg. Therapeutic effects of IMM40H at the dose of 3 mg/kg also appeared earlier than that of bortezomib at the dose of 0.5 mg/kg. Interestingly, combination of IMM40H and IMM01 (a SIRPα-IgG1 Fc fusion protein targeting CD47) generated significant therapeutic synergy in models of A498 kidney cancer and Raji lymphoma...IND of IMM40H has been approved in China and US. This antibody is now in a phase 1 study in patients with advanced malignancies expressing CD70.

Thus, cusatuzumab/azacitidine appears generally well tolerated and shows preliminary efficacy in this setting. Investigation of cusatuzumab combined with current standard-of-care therapy, comprising venetoclax and azacitidine, is ongoing.

P1/2, N=38, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed

No dose limiting toxicity was observed during the study period. The combination of cusatuzumab and azacitidine is generally well tolerated in Japanese participants and further exploration of this combination is warranted.

P1/2, N=38, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2022 --> Oct 2022

Pre-clinical studies using an anti-CD70 antibody (ARGX-110) demonstrated indirect anti-tumor effects mediated by NK cells... CD70 is an attractive target with immunotherapy potential against OS. We showed that CD70-CAR NK cells are effective against OS cells in vitro compared to control NK cells. CD70-CAR NK killing does not correlate with an increased level of CD70 expression.

The TNF-alpha family member CD70 has emerged as a promising surface target antigen in AML after high complete response rates (CR) were seen in a Phase 1 trial of the CD70 antibody cusatuzumab (Riether et al, Nature Medicine 2020). Our findings demonstrate that natural-ligand binding domains of CARs targeting CD70 in AML can be effective but require mechanisms to overcome surface cleavage. CD70-targeted CARs comprised of a fusion of truncated CD27 to a CD8 hinge and transmembrane domain have promise in patients with AML, with and without combination with azacitidine.

Cusatuzumab administered in combination with venetoclax and azacitidine to elderly patients with untreated AML was generally well tolerated and demonstrated a safety profile consistent with that previously reported with venetoclax-azacitidine, with the addition of generally manageable IRRs. Response rates support an additive effect of cusatuzumab to the standard of care with potential for improved clinical outcomes. However, further clinical trials are needed for validation of these initial results.

Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.

P1/2, N=38, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jul 2021 --> Apr 2022

Limited activity of cusatuzumab in advanced NPC was observed. Combination therapies of cusatuzumab and other types of therapy should be explored for the improvement of activity in NPC and other CD70-expressing malignancies.

P1/2, N=38, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jul 2021 --> Apr 2022

Cusatuzumab synergized with a hypomethylating agent in older patients with acute myeloid leukemia.

Gemtuzumab ozogamicin, a CD33 directed antibody-drug conjugate, has provided the proof of concept for the potential efficacy of monoclonal antibody-based therapies in AML...The first-in-class anti-CD47 antibody magrolimab and anti-CD70 antibody cusatuzumab in combination with hypomethylating agent (HMA) azacitidine, in newly diagnosed AML, and flotetuzumab, a bispecific DART® (dual-affinity retargeting) antibody to CD3ε and CD123 as salvage option in relapsed/refractory AML appear promising...Ongoing research will define the choice of an appropriate complementary therapeutic agent in antibody-based combination therapy, and whether one or more than one antigen should be simultaneously targeted. Further studies will likely refine the role of antibody-based therapy in post hematopoietic cell transplant setting.

P1/2, N=38, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Dec 2020 --> Jul 2021

Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). No dose-limiting toxicities were reported and the maximum tolerated dose of cusatuzumab was not reached. Importantly, cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.

P1/2, N=99, Completed, Janssen Research & Development, LLC | Active, not recruiting --> Completed | Trial completion date: Dec 2020 --> Jul 2020

Cusatuzumab synergized with a hypomethylating agent in older patients with acute myeloid leukemia.

P1/2, N=99, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Jul 2020 --> Dec 2020

CD70 (CD27 ligand) is a candidate target antigen for T cell lymphomas and has been is the subject of clinical trials using an enhanced ADCC antibody (ARGX-110). Consistent with these prior observations, CTX130 exhibited high potency in vitro and in vivo against T cell lymphoma cells across a range of CD70 antigen density and representing different types of T cell lymphomas such as Sezary syndrome and cutaneous T cell lymphoma (CTCL). CTX130 may thus be a valid therapeutic to evaluate in T cell lymphoma patients.

Elderly or unfit AML patients not eligible for intensive chemotherapy are treated in a palliative setting with hypomethylating agents (HMA) or low dose Ara-C, but responses are modest and not durable...The therapeutic potential of targeting CD70-expressing LSCs in presence and absence of HMA was assessed using the anti-CD70 ADCC-optimized monoclonal antibody (mAb), cusatuzumab, and an effector-dead anti-CD70 mAb in colony formation and re-plating assays as well as patient-derived xenograft models (Silence et al, 2014)...In combination with azacitidine, cusatuzumab induced CR/CRi in 10 out of 12 patients...Conclusions Blocking CD70/CD27-signaling and targeting CD70-expressing LSCs by the ADCC-optimized mAb, cusatuzumab, eliminated LSCs in vitro and in xenotransplantation experiments. In a phase 1 study promising activity of cusatuzumab in combination with HMA was observed in AML patients, in which translational data indicate that cusatuzumab selectively eliminates CD70-expressing LSCs.