Focusing on discovering and developing a pipeline of novel antibody-drug conjugates or ADCs based on its proprietary Dolaflexin® platform, Mersana Therapeutics’ Investigational New Drug (IND) application for XMT-1536, was cleared to begin Phase I clinical trials.

The U.S. Food and Drug Administration (FDA) IND clearance is the second for Mersana’s Novel Dolaflexin ADC platform within the past year.

“We are excited to be moving XMT-1536 into clinical development as a first-in-class and potentially best-in-class ADC against NaPi2b, a target with outstanding properties for ADC development on the Dolaflexin platform,” noted Donald A. Bergstrom, MD, Ph.D, Chief Medical Officer.


“Currently, patients with advanced epithelial ovarian cancer, non-squamous NSCLC and other NaPi2b-expressing tumors have a poor prognosis, and there’s a clear need for better treatment options. We look forward to beginning the clinical investigation of XMT-1536, which has shown promising results in preclinical models,” Bergstrom added.

Mersana’s proprietary auristatin AF-HPA is capable of controlled bystander-effect killing, resulting in efficacy in tumors with heterogeneous antigen expression… it is metabolized intra-tumorally to an active non-permeable metabolite to enable greater systemic tolerability…

Targeting NaPi2b
XMT-1536 is a first-in-class ADC targeting  the transmembrane sodium-phosphate transporter NaPi2ba (SLC34A2) which is a clinically validated ADC target broadly expressed in epithelial ovarian cancer, non-squamous non-small cell lung cancer (NSCLC), as well as a number of other tumor types. [1]

Photo 1.0: Donald A. Bergstrom, MD, Ph.D, Chief Medical Officer, Mersana Therapeutics.

The investigational agent is comprised of Mersana’s Dolaflexin platform conjugated to a proprietary NaPi2b antibody. Each antibody molecule carries 10-15 molecules of Mersana’s proprietary DolaLock payload, resulting in a balance of meaningful preclinical efficacy and preclinical tolerability.

Results from exploratory multiple dose toxicology study showed no evidence of significant pulmonary toxicity (primary tissue with NaPi2b expression) and no neutropenia at 2 times the payload dose that induced fatal neutropenia and sepsis in nonclinical studies of Genentech’s NaPi2b vcMMAE (Lifastuzumab vedotin, developed by Genentech using Seattle Genetics vcMMAE platform).

In preclinical studies, XMT-1536 induced greater than 50% median tumor regression in 10/19 (53%) primary patient-derived ovarian cancer xenograft models unselected for NaPi2b protein expression, with 10/12 (83%) tumor responses in NaPi2b-expressing models. In patient-derived NSCLC xenograft models, XMT-1536 achieved durable tumor regressions in 6/9 (75%) tested models.

Mersana’s proprietary auristatin F-HPA (AF-HPA) drug payload promotes potent cell killing upon initial release of the agent. This proprietary payload is specifically designed to control cell killing of the surrounding tumor cells through bystander effect and increase efficacy in the tumor environment and as well as improve systemic tolerability.

However, this payload is further processed in the cell to a metabolite which remains strongly cytotoxic but loses the ability to cross the cell membrane and as a result, becomes trapped and loses bystander capability.

This feature, which Mersana refers to as ‘DolaLock,’ makes it possible to capture the benefits of the bystander effect while minimizing potential toxicities to healthy tissues.

“The clearance of this IND, our second in a year, marks an important milestone for the company as we continue to move our novel pipeline of product candidates into the clinic,” said Anna Protopapas, President and Chief Executive Officer of Mersana.

“This achievement is a result of our dedicated employees who are focused on executing on our important mission of creating therapies with meaningful clinical benefit for patients,” she added.