amatuximab (MORAb-009)

Therapeutically, it caused dose-dependent tumor regression (TGI: 58% at 50 kBq; 92% at 150 kBq) and prolonged survival (>60 days vs. 0-1% in controls, p < 0.001). &lsqb;225Ac]Ac-Macropa-PEG6-Amatuximab is stable, selective, and therapeutically effective, demonstrating Macropa-based 225Ac chelation as a stable platform for targeted α-therapy of PDAC.

Quantitative ex vivo fluorescence analysis of excised xenografts demonstrated that combining ch10D7ICG and amatuximabICG enhances tumor-associated fluorescence by 2.8- to 12.5-fold compared with either agent alone. The results support the potential of dual-targeted, antibody-based fluorescence imaging for enhanced intraoperative visualization and excision of PDAC, including for tumors with heterogeneous expression of either or both of the targeted receptors CDCP1 and MSLN.

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.

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.

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.

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.

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.

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.

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.

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.