Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models

Abstract

Despite the recent advances in the treatment of ovarian cancer, it remains an area of high unmet medical need. Epithelial ovarian cancer is associated with high levels of mesothelin expression, and therefore, mesothelin is an attractive candidate target for the treatment of this disease. Herein, we investigated the antitumor efficacy of the mesothelin-targeting antibody-drug conjugate (ADC) anetumab ravtansine as a novel treatment option for ovarian cancer in monotherapy and in combination with the antitumor agents pegylated liposomal doxorubicin (PLD), carboplatin, copanlisib and bevacizumab. Anetumab ravtansine showed potent antitumor activity as a monotherapy in ovarian cancer models with high mesothelin expression. No activity was seen in mesothelin-negative models. The combination of anetumab ravtansine with PLD showed additive anti-proliferative activity in vitro, which translated into improved therapeutic in vivo efficacy in ovarian cancer cell line- and patient-derived xenograft (PDX) models compared to either agents as a monotherapy. The combination of anetumab ravtansine with the PI3Kα/δ inhibitor copanlisib was additive in the OVCAR-3 and OVCAR-8 cell lines in vitro, showing increased apoptosis in response to the combination treatment. In vivo, the combination of anetumab ravtansine with copanlisib resulted in more potent antitumor activity than either of the treatments alone. Likewise, the combination of anetumab ravtansine with carboplatin or bevacizumab showed improved in vivo efficacy in the ST081 and OVCAR-3 models, respectively. All combinations were well-tolerated. Taken together, these data support the development of anetumab ravtansine for ovarian cancer treatment and highlight its suitability for combination therapy with PLD, carboplatin, copanlisib, or bevacizumab.

Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers

“…Indeed, in additional preclinical models, increased activity of BAY 2287411 over existing therapies for mesothelioma and ovarian cancer was observed (data not shown). Interestingly, and in line with a study showing that MSLN expression is recycled to the surface within 48 h after treatment (18), it was observed that MSLN expression was still detectable in BAY 2287411-treated tumors up to 54 days postdosing.…”

“…Intracellularly, MSLN can activate NFkB, MAPK, and PI3K signaling pathways, thereby promoting cell proliferation and resistance to apoptosis (15). The restricted expression of MSLN on healthy tissues, combined with the high expression on several solid cancers renders it an attractive tumor antigen for targeted cancer therapy and several preclinical and clinical approaches are currently being pursued including CAR-T cells, vaccines, antibodies (amatuximab), recombinant immunotoxins (SS1P, and RG7787) as well as antibody drug conjugates (anetumab ravtansine/BAY 94-9343; aMSLN-MMAE (h7D9.v3), and MDX-1204 (14,(16)(17)(18).…”

Engineered Fn3 protein has targeted therapeutic effect on mesothelin‐expressing cancer cells and increases tumor cell sensitivity to chemotherapy

“…Further, the Fn3 protein engineered to bind MSLN increases the sensitivity of tumor cells to a common chemotherapeutic agent when used as a combination therapy. In recently reported work, treatment with anetumab ravtansine, a MSLN‐specific antibody‐drug conjugate, not only inhibited tumor growth in ovarian cancer models as a monotherapy, but also exhibited an additive effect when used in combination with targeted agents and standard chemotherapeutics (Quanz et al, ). Together, this current report and the recent results of related research validate that molecules developed to target MSLN are promising for both monotherapy and combination therapy for patients who do not currently have any targeted treatment options.…”

“…Promising results from preclinical and clinical trials to target MSLN with antibodies, antibody derivatives, immunotoxins, antibody‐drug conjugates, and CAR‐T cells for therapy demonstrate the promise of MSLN‐targeting methods (El‐Behaedi et al, ; Golfier et al, ; Ho, Feng, Fisher, Rader, & Pastan, ; Quanz et al, ; Adusumilli et al, ; Morello, Sadelain, & Adusumilli, ; Tang et al, ). However, no MSLN‐targeting molecules are currently approved for routine clinical use.…”

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

“…Anetumab ravtensine (AR) (Bayer, Leverkusen, Germany) is an ADC that contains a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a reducible disulfide linker [19]. Preclinical studies have shown potent antitumor activity in adult solid tumor models [19,20], which has led to the development of a number of Phase I and II clinical trials for adults with aggressive mesothelin-expressing solid tumors alone and in combination therapy [17]. Mesothelin was also shown to be expressed in pediatric AML cells [21].…”