On March 15, 2021 Mersana Therapeutics, Inc. (Nasdaq: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported the publication of two manuscripts in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Mersana Therapeutics, MAR 15, 2021, View Source [SID1234576649]). The manuscripts describe the preclinical development of the Dolaflexin ADC platform and XMT-1536, now called upifitamab rilsodotin (UpRi), Mersana’s first-in-class NaPi2b-targeted ADC developed using this platform.
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The first of these articles, "Dolaflexin: A Novel Antibody-Drug Conjugate Platform Featuring High Drug Loading and a Controlled Bystander Effect," provides detailed characterization of Dolaflexin, the Company’s novel ADC technology which is designed to overcome limitations of the most common ADC platforms with two key features: a higher drug-antibody ratio and a proprietary auristatin with a controlled bystander effect. The proprietary, cell permeable DolaLock payload auristatin F-hydroxypropylamide (AF-HPA) undergoes metabolic conversion to the highly potent but less cell-permeable auristatin F (AF) to balance the bystander effect through drug trapping within target cells and is designed to improve efficacy while avoiding the severe neutropenia, peripheral neuropathy and ocular toxicities commonly observed with other anti-tubulin ADC payloads.
The second article, "The Dolaflexin-based antibody-drug conjugate XMT-1536 targets the solid tumor lineage antigen SLC34A2/NaPi2b," describes pre-clinical discovery and characterization of UpRi, Mersana’s lead clinical-stage Dolaflexin ADC. NaPi2b is a sodium phosphate transporter expressed in a variety of human tumors. The broad expression of NaPi2b in epithelial ovarian cancer and lung adenocarcinoma is described, as is UpRi’s ability to selectively target human NaPi2b. In vivo data in preclinical models revealed target expression-dependent activity in a series of NSCLC adenocarcinoma patient derived xenografts (PDX) as well as profound activity in a panel of ovarian adenocarcinoma PDXs. Pharmacokinetic analyses showed approximately dose-proportional exposure across animal species as well as high serum stability of the conjugate, and systemic free AF-HPA and AF concentrations remaining low in all animal species.
"These studies demonstrate the differentiated design and advantages of the Dolaflexin platform in preclinical studies and its potential for creating a new and improved class of ADCs," said Timothy Lowinger, Ph.D., Chief Science and Technology Officer of Mersana Therapeutics. "In addition, the extensive preclinical data with UpRi, created by conjugating a NaPi2b-targeting antibody with Dolaflexin, gave us the confidence to proceed into the clinic. UpRi has since exhibited promising activity and a favorable tolerability profile in ongoing proof-of-concept studies in heavily pre-treated ovarian cancer patients with significant unmet medical need. We are very proud of the dedication and commitment of our team who have worked tirelessly to bring Dolaflexin and UpRi forward."
UpRi is in the expansion portion of a Phase 1 proof-of-concept clinical study in patients with ovarian cancer and NSCLC adenocarcinoma. Mersana intends to initiate a single-arm registration enabling strategy in platinum resistant ovarian cancer (UPLIFT) in the first quarter of 2021 as well as an umbrella combination study in earlier lines of therapy (UPGRADE) in the third quarter of 2021. More information on the ongoing clinical study can be found at clinicaltrials.gov (NCT03319628).