A Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma

This study was originally designed as a multicenter, double-blind, randomized, parallel-group study, using a placebo control or amatuximab 5 milligrams per kilogram (mg/kg), administered weekly, designed to evaluate the safety and efficacy of amatuximab in combination with pemetrexed and cisplatin in participants with unresectable Malignant Pleural Mesothelioma (MPM) who have not received prior systemic therapy.
Per a business decision made by the Sponsor, participants who were randomized to amatuximab and were still on active treatment at the time of the protocol amendment may have consented to continue to receive weekly treatment with amatuximab until disease progression or intolerable toxicity at the discretion of the principal investigator. Participants randomized to placebo or who were in follow-up at the time of the amendment have been discontinued from the study.

Start Date03 Nov 2015

Sponsor / Collaborator

Morphotek, Inc.

EUCTR2014-003812-36-IT / Unknown statusPhase 2

A Randomized, Double-blind, Placebo-Controlled, Phase 2 Study to Assess the Efficacy and Safety of Farletuzumab (MORAb 003) in Combination with Carboplatin plus Paclitaxel or Carboplatin plus Pegylated Liposomal Doxorubicin (PLD) in Subjects with Low CA125 Platinum-Sensitive Ovarian Cancer.

Start Date22 Jul 2015

Sponsor / Collaborator

Morphotek, Inc.

EUCTR2014-003812-36-ES / Not yet recruitingPhase 2

Start Date29 May 2015

Sponsor / Collaborator

Morphotek, Inc.

100 Clinical Results associated with Morphotek, Inc.

0 Patents (Medical) associated with Morphotek, Inc.

Literatures (Medical) associated with Morphotek, Inc.

01 Jul 2019·Cancer Research

Abstract 2370: Synergistic effect of carboplatin on farletuzumab (FAR) tumor cell killing via downregulation of the humoral immunosuppressive CA125 protein and enhanced antibody dependent cellular cytotoxicity (ADCC)

Author: Fulmer, James ; McDonough, Jennifer ; Grasso, Luigi ; Nicolaides, Nicholas C. ; Kline, J. Bradford ; Furuuchi, Keiji

AbstractFarletuzumab (FAR) is a humanized monoclonal antibody (mAb) that targets folate receptor alpha (FRA), a cell surface protein highly overexpressed on a large number of cancers. Clinical evidence suggests that FAR enhances the anti-tumor effects of carboplatin and taxane in ovarian cancer patients whose tumors express low CA125 levels. In light of the recent evidence that CA125 has a direct effect on suppressing the humoral immune mechanisms [antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC)] of FAR (1, 2) and the findings that chemotherapeutic agents can enhance the ADCC activity of certain mAbs, we tested the potential synergistic effects that carboplatin may have on FAR immune effector function. Here we show the immunosuppressive effects that CA125 has on FAR-mediated tumor cell killing in vivo and demonstrate that carboplatin is able to suppress cell surface CA125 expression leading to enhanced FAR ADCC on FRA-expressing ovarian tumor cells. CA125 has been previously found to suppress FAR-mediated tumor cell killing in vitro. To determine its effect in vivo, we tested single agent FAR against isogenic tumor cells in mouse xenografts. OVCAR-3 is a FRA positive ovarian tumor cell line that expresses high levels of CA125 on its cell surface. A CA125 shRNA knockdown line (OV-KD) has been previously generated and shown to be more susceptible to FAR ADCC than its parental counterpart. Xenograft studies using these lines found that FAR had significant single agent tumor killing in the OV-KD xenografts in contrast to OVCAR-3 xenografts. We next tested FAR in vivo killing when used in combination with carboplatin. These data showed that carboplatin had a synergistic effect when combined with FAR treatment as compared to single agent treatment alone. To determine if this mechanism involved enhanced ADCC, we conducted similar studies in vitro whereby OVCAR-3 cells were treated with a sublethal concentration of carboplatin for 72 hrs, washed and then tested for FAR ADCC killing. These data found that FAR had enhanced ADCC activity on carboplatin treated cells as compared to untreated cells. Finally, to explore the potential mechanism by which this effect may occur, we examined the steady-state levels of both the mannose-6-phosphate receptor (M6PR), reported to be upregulated by chemotherapeutic drugs leading to enhanced ADCC via higher granzyme B uptake and the CA125 immunosuppressive factor. Our data found that both M6PR and CA125 expression were significantly suppressed following carboplatin exposure. These data support a mechanism by which carboplatin may enhance the humoral immune response for FAR and potentially other anti-tumor mAbs via downregulation of the immunosuppressive CA125 protein. 1. OncoTarget 8:66747-57, 20172. 2. EJI 201847707, 2018Citation Format: J. Bradford Kline, Keiji Furuuchi, James Fulmer, Jennifer McDonough, Luigi Grasso, Nicholas C. Nicolaides. Synergistic effect of carboplatin on farletuzumab (FAR) tumor cell killing via downregulation of the humoral immunosuppressive CA125 protein and enhanced antibody dependent cellular cytotoxicity (ADCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2370.

01 Jun 2019·eBioMedicineQ1 · MEDICINE

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation

Q1 · MEDICINE

ArticleOA

Author: Clee, Susanne M ; Lei, Victor ; Carpentier, André C ; Petrus, Paul ; Kwon, Michelle M ; Johnson, James D ; Fernandez, Tara L ; Catrina, Sergiu-Bogdan ; Noll, Christophe ; Rydén, Mikael ; Albone, Earl ; Virtanen, Kirsi ; Kieffer, Timothy J ; Conway, Edward M ; O'Shannessy, Daniel J ; Zheng, Xiaowei ; Karunakaran, Subashini ; Laine, Jukka ; Huang, Jenny L ; Safikhan, Nooshin Seyed

BACKGROUNDA positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored.METHODSThe role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice.FINDINGSCD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance.INTERPRETATIONCD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

01 Dec 2018·Molecular Cancer Therapeutics

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

Article

Author: Cheng, Xin ; Grasso, Luigi ; Fang, Frank ; Kuc, Megan ; Milinichik, Andrew Z. ; Li, Jing ; Majumder, Utpal ; Fernando, Danielle ; Verdi, Arielle C. ; Rybinski, Katherine A. ; Tanaka, Keigo ; Furuuchi, Keiji ; Maddage, Christopher J. ; Uenaka, Toshimitsu ; Fernando, Shawn ; Albone, Earl F.

AbstractMicrotubule-targeting agents (MTA) have been investigated for many years as payloads for antibody–drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.

100 Deals associated with Morphotek, Inc.

100 Translational Medicine associated with Morphotek, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Gimsilumab ( GM-CSF )	Nasopharyngeal Neoplasms More	Phase 2
MORAb-050 ( GM3 )	Melanoma More	Preclinical
MORAb-048 ( SEB )	Staphylococcal Infections More	Preclinical
HuMAb-154 ( SEB )	Staphylococcal Infections More	Preclinical
TM-604	Neoplasms More	Discontinued

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