amatuximab (MORAb-009) / Eisai - LARVOL DELTA

Preclinical evaluation of 89Zr/177Lu-labeled amatuximab for theranostic application in pancreatic ductal adenocarcinoma. (PubMed, Int J Pharm) - "Furthermore, in vivo studies indicated that 177Lu-DOTA-amatuximab exhibited limited side effects. The development of 89Zr/177Lu-labeled amatuximab may provide novel insights into the formulation of precision diagnostic and therapeutic strategies for MSLN- overexpressing tumors, including PDAC."

IO biomarker • Journal • Preclinical • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • MSLN

Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity. (PubMed, Cytotherapy) - "These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN."

CAR T-Cell Therapy • Journal • Gastrointestinal Cancer • Hepatology • Mesothelioma • Oncology • Pancreatic Cancer • Solid Tumor

Rapid nanobody-based imaging of mesothelin expressing malignancies compatible with blocking therapeutic antibodies. (PubMed, Front Immunol) - "The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLN tumours. We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates."

Journal • Oncology • MSLN • MUC16

Structures of Cancer Antigen Mesothelin and Its Complexes with Therapeutic Antibodies. (PubMed, Cancer Res Commun) - "The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously...The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies."

IO biomarker • Journal • Oncology • MSLN • MUC16

Immunotherapy in MPM (WCLC 2017) - P2,P3; "...Finally, the JAVELIN study of Avelumab, a PD-L1 inhibitor, in patients with prior therapy reported a PR rate of 9.4% and DCR of 57%(6)...Ongoing clinical trials of single agent checkpoint blockade included the randomised phase III CONFIRM trial, comparing nivolumab with placebo in 336 previously treated patients (NCT03063450), and the randomised phase III PROMISE-Meso study, comparing pembrolizumab with chemotherapy in the second line (plus) setting in 142 patients (NCT02991482)...The completed NIBIT-Meso 1 trial is a phase II study of tremelimumab and durvalumab for which results are likely to be available soon (NCT02588131), with a further phase II trial of the same agents and similar design open in the USA (NCT03075527)...Two single arm phase II clinical trials of identical design are combining cisplatin and pemetrexed first line chemotherapy with durvalumab, one Australian (ACTRN 12616001170415) and one in the USA (NCT02899195). A randomised phase II study in Canada

Biomarker • CAR T-Cell Therapy • Checkpoint inhibition • Clinical • Mesothelioma

Con - Raphael Bueno Is Right (It Does Not Work) (IASLC-WCLC 2019) - P1, P2, P2/3, P3; "...Combination chemotherapy with platinum/antifolate –either pemetrexed or raltitrexed- is the only standard of care 1st line treatment with proven improvement of survival, which varies according to series and patient selection between 12-16 months median overall survival (mOS), with corresponding 1 year survival rate of 50-60%...The randomized DETERMINE trial evaluated in 564 patients the anti–CTLA-4 antibody tremelimumab versus placebo in second or third line and found no benefit in outcome (hazard ratio 0.92; p = 0.408). Results from the anti–PD-1 or anti–PD-L1 trials with nivolumab, pembrolizumab and durvalumab are fairly consistent with a response rate of 19-30%, a median PFS of 3.5 – 6.0 months and mOS of 12-18 m, all uncontrolled in selected patients with good prognostic features...The DREAM trial, a single-arm, open-label phase II trial of durvalumab with cisplatin/pemetrexed, followed by durvalumab maintenance therapy for 1 year...The phase III CheckMat

IO biomarker • PD(L)-1 Biomarker • Tumor mutational burden • Lung Cancer • Mesothelioma • Oncology • Solid Tumor • Thoracic Cancer

The development of HK013, a bispecific antibody targeting MSLN and CD137, for the treatment of MSLN+ solid tumors (AACR 2022) - "R3C7 blocks the binding of MORAb-009 to MSLN, while R2G12 does not...The bispecific formats are related to the Fc receptor-mediated non-specific activation of CD137 signal, which may potentially cause safety issue. The strong antitumor activity and the lowest non-specific activation of CD137 signal of HK013 makes it the candidate worthwhile of further evaluation of its safety and efficacy."

Late-breaking abstract • Breast Cancer • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • IFNG • MSLN • MUC16 • TNFRSF9

T Cell Engaging Bispecific Antibodies Produce Durable Response in Mesothelin-Positive Patient-Derived Xenograft Models of Pediatric AML (ASH 2021) - "Antibody single-chain variable region (scFv) sequences derived from amatuximab recognizing MSLN and from either blinatumomab or AMG330 targeting CD3 were used to engineer and express two MSLN/CD3-targeting BsAbs: MSLN AMA -CD3 L2K and MSLN AMA -CD3 AMG respectively...Chemotherapy (DA) consisted of 3 doses of 1.5 mg/kg daunorubicin iv and 5 doses of 50 mg/kg cytarabine ip...Conclusion These data validate the efficacy of MSLN-targeting BsAbs in PDX models with endogenous MSLN expression. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • B2M • MSLN

Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies. (PubMed, Cancers (Basel)) - "Using antibody single-chain variable region (scFv) sequences derived from amatuximab-recognizing MSLN, and from either blinatumomab or AMG330 targeting CD3, we engineered and expressed two MSLN/CD3-targeting BsAbs: MSLN-CD3 and MSLN-CD3, respectively. These data validate the in vivo efficacy and specificity of MSLN-targeting BsAbs. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients."

Clinical • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • MSLN

Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model. (PubMed, Invest New Drugs) - "In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • MET • MSLN

Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells. (PubMed, BMC Cancer) - "Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • ALDH1A1 • CD44 • MET • MSLN

Dual-targeting mesothelin/CD47 bispecific antibodies for tumor-directed blockade of CD47 in solid cancer (AACR 2018) - "...With various MSLN-positive human cancer cell lines, MSLN/CD47 biAbs demonstrate significantly enhanced cancer cell killing by ADCC and ADCP as compared to the corresponding anti-MSLN monoclonal antibody format (mAbs) as well as to amatuximab, a therapeutic anti-MSLN mAb (currently in Phase II clinical trials for mesothelioma)...Taken together, we conclude that MSLN/CD47 biAbs should allow for efficacious, yet safe, targeting of CD47 in multiple solid tumor indications in the clinic. More generally, our data support the concept of tumor-directed blockade of CD47 with biAbs as a novel way of improving the efficacy of antibody-based cancer therapies."

Gastric Cancer • Mesothelioma

[VIRTUAL] Therapeutic Targeting of Mesothelin in Acute Myeloid Leukemia with Chimeric Antigen Receptor T Cell Therapy (ASH 2020) - "The VH and VL sequences from Amatuximab were used to create the scFv domain of the standard CAR (41-BB and CD3Zeta)... In this study, we demonstrate that mesothelin is a viable therapeutic target and a potential diagnostic biomarker in AML. We show that MSLN CAR T cells were highly effective in eliminating MSLN-positive AML cells in vitro and in vivo. Shedding contributes to the loss of mesothelin antigen and provides a source of soluble mesothelin that may interfere with antibody-based therapies, including CAR T cells."

CAR T-Cell Therapy • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • Transplantation • CD34 • MSLN

[VIRTUAL] Targeting a membrane proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on tumor cells (ITOC-I 2020) - "However, an anti-MSLN monoclonal antibody (mAb), amatuximab, has demonstrated only limited efficacy in clinical trials...Conclusions This study demonstrated that when designing antibody-based molecules, the targeted region on a tumor associated antigen needs to be carefully considered to ensure maximal effector function. In the context of MSLN-positive solid tumors, we showed that an approach targeting a membrane-proximal epitope coupled to a CD47-blocking arm afforded an improved ADCC and ADCP profile, translating into increased in vivo efficacy."

IO Biomarker • Gastric Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • FCGR2A • MSLN

Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection. (PubMed) - Cancer Chemother Pharmacol - "In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS."

Journal • Biosimilar • Mesothelioma • Oncology

Eisai: Information Meeting 2016 (Eisai) - Anticipated launch for mesothelioma globally beyond FY2020

Anticipated launch • Mesothelioma • Oncology

Mesothelin Targeting Bites for Pediatric AML: In Vivo Efficacy and Specificity (ASH 2019) - "Using scFv sequences derived from Amatuximab, which recognizes the N-terminal domain of the GPI-linked ectodomain of MSLN, targeting region 1 of MSLN, and from Blinatumomab/AMG-330 targeting CD3, we engineered and expressed two kinds of BiTE molecules – a canonical BiTE and an IgG BiTE, a larger molecule with improved serum half life in vivo. 1H), suggesting that IgG BiTE was far more efficacious than canonical BiTEs (P<0.01). Taken together, these data indicate that MSLN-targeting BiTEs could be used as novel immunotherapy for pediatric AML with MSLN expression."

IO Biomarker • B2M • MLL • MSLN

Amatuximab for High Mesothelin Cancers (clinicaltrials.gov) - P0; N=7; Terminated; Sponsor: National Cancer Institute (NCI); Completed ➔ Terminated

Clinical • Trial termination

Amatuximab for High Mesothelin Cancers (clinicaltrials.gov) - P; N=7; Terminated; Sponsor: National Cancer Institute (NCI); Phase classification: P=N/A ➔ P

Clinical • Phase classification

CA125 suppresses amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients. (PubMed, Cancer Biol Ther) - "To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125."

Clinical • Journal

Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens. (PubMed, Contrast Media Mol Imaging) - "We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients...Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers."

Journal

Selectively targeting CD47 with bispecific antibody to efficiently eliminate mesothelin-positive solid tumors (AACR 2019) - "...Clinical efficacy has been achieved in patients with Non-Hodgkin lymphoma (NHL) treated with a combination of the anti-CD20 monoclonal antibody (mAb), rituximab, and the anti-CD47 mAb, Hu5F9-G4...An anti-CD47xMSLN bsAb with a fully functional IgG1 Fc domain has been generated and tested for efficacy and safety in vitro and in vivo using cell-based assays and animal models.With a panel of human MSLN+ target cells, the bsAb kills more efficiently through Ab-dependent cellular phagocytosis (ADCP) and cell-mediated cytotoxicity (ADCC) as compared to the anti-MSLN mAb, amatuximab... Selective CD47 targeting on tumor cells with an anti-CD47xMSLN bsAb showed efficient killing of MSLN+ tumor cells in vitro and in vivo. A study in non-human primates administered weekly a therapeutically relevant dose over 28 days was well tolerated demonstrating no adverse hematological profiles."