BUILDING THE BACKBONE

Mersana’s approach to building novel drug conjugates starts with our Fleximer polymer, which can dramatically improve drug solubility and pharmacokinetics, reduce immunogenicity and optimize drug load. Our Fleximer polymer is uniquely biodegradable, well tolerated with a favorable safety profile and has been clinically validated. The Fleximer polymer serves as the backbone for our drug conjugates. We customize the size of the backbone based on the type and quantity of therapeutic payloads, as well as the nature of the targeting protein being attached.

CUSTOM-DESIGNED LINKERS

We determine which and how many linkers to use to attach the payload to the backbone. Mersana’s diverse array of linker chemistries allows us to arm our drug conjugates with significantly higher loads of anti-cancer agents than conventional ADC technologies, as well as to potentially arm a single ADC with a combination of payloads. The custom-designed linkers allow us to control the rate, mechanism and localization of drug release, potentially increasing efficacy and minimizing off-target side effects.

Using a chemically distinct linker from those used to attach the therapeutic payload, we then attach an antibody, or alternative targeting moiety such as an antibody fragment, to the backbone. The ability to attach a variety of targeting agents to the Fleximer backbone allows us to choose the one that will most effectively reach, bind to and penetrate the tumor cell, while sparing healthy cells. By using separate linker chemistries to attach the targeting agent and drug payload, we can choose the best linkers for each task.

MAXIMIZING THERAPEUTIC BENEFIT

While in the bloodstream, our Fleximer polymer protects the drug payload, ensuring stability. Through optimized design and careful control of numerous parameters, our ADCs are preferentially taken up by cancer cells, accumulating and persisting in the tumors to deliver a prolonged therapeutic effect. Once the drug payload has been released, the Fleximer polymer and linkers biodegrade into safe byproducts, further supporting the potential safety benefits of this novel approach.

Mersana’s Fleximer platform represents an evolutionary leap in ADC technology, allowing us to overcome many of the limitations of current ADC technologies. Using our proprietary Fleximer polymer and linker chemistries, we can custom design a drug conjugate with a unique combination of properties aimed specifically at attacking a particular type of cancer. By engineering a drug conjugate with industry-leading payloads of anti-cancer agents and precisely controlling when, where and how those agents are released, Mersana’s ADC therapies have the potential to more effectively treat broader populations of cancer patients while minimizing undesired side effects.

Significantly higher Drug-to-Antibody ratio (DAR) (20+ versus 3-4 with traditional technologies) resulting in higher efficacy in head to head studies

Strong efficacy in low expressing tumors for a variety of targets not amenable to traditional ADCs

Robust data supporting a variety of payload classes and mechanisms-of-action allowing a more appropriate match of drug to tumor type

Can be deployed with a variety of  targeting moieties beyond antibodies for improved tumor penetration of solid tumors and thereby enhanced efficacy

Our lead platform, incorporated into our first two products, is Dolaflexin.   The Dolaflexin platform is designed to increase the efficacy, safety and tolerability of ADCs by overcoming key limitations of existing technologies based on direct conjugation of a payload molecule to an antibody. Dolaflexin consists of Fleximer, a biodegradable, highly biocompatible, water soluble polymer, to which are attached multiple molecules of our proprietary auristatin drug payload, using a linker specifically optimized for use with our polymer. The high-water solubility of the Fleximer polymer compensates for the low solubility of the payload, surrounding the payload and protecting it from aggregation and maintaining stability in circulation. Multiple molecules of this Dolaflexin polymer-drug conjugate can then be attached to an antibody of choice, which significantly increases the payload capacity of the resulting ADC. This approach differs from most other ADC technologies where the payload is directly conjugated to the antibody via a linker. Using our Dolaflexin platform, we have been able to generate ADCs with Drug-to-Antibody Ratio (DAR) between 12 to 15 while maintaining acceptable pharmacokinetics and drug-like properties in animal models. This represents a three to four-fold increase in DAR relative to traditional ADC approaches.

We believe its properties will enable us to develop ADCs with an improved therapeutic index that may broaden the scope of addressable cancer patients for which ADC therapies are amenable.

IMPROVED LINKER STABILITY: There are two important linkers contributing to the stability of a Dolaflexin ADC: a non-cleavable linker attaching the Fleximer to the antibody and a cleavable linker attaching the payload to the Fleximer. The Fleximer provides for a highly hydrophilic and homogeneous microenvironment that stabilizes the payload-linker in circulation. However, the cleavable nature of the payload-linker results in rapid release of the payload upon internalization into the tumor cell.

HIGHER DRUG-TO-ANTIBODY RATIO: Dolaflexin consists of Fleximer conjugated to an average of four molecules of our proprietary auristatin payload. Our ADCs typically consist of an average of three to four Dolaflexin units attached to each antibody, which allows us to achieve significantly higher DAR compared to other ADC approaches. For example, our lead proprietary product candidates, XMT-1522 and XMT-1536, each carry between 12 to15 payload molecules per antibody, which we believe will result in greater efficacy than traditional ADCs with a lower DAR. Importantly, Fleximer is extremely water soluble, which helps maintain the drug-like properties and pharmacokinetics of the ADC in animal models even at relatively high DARs.

EXPANDED RANGE OF ADDRESSABLE ANTIGEN EXPRESSION LEVELS: The higher DAR enabled by our Dolaflexin platform results in more chemotherapeutic payload being released into the tumor cell for every binding and internalization event. As a result, we have demonstrated in animal models that Dolaflexin ADCs have efficacy against tumors with lower levels of antigen expression where traditional ADCs have not been effective.

CONTROLLED BYSTANDER EFFECT: Our proprietary auristatin drug payload promotes potent cell killing upon initial release of the ADC and has the ability to kill surrounding tumor cells through the bystander effect.  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 we refer to as DolaLock, allows us to capture the benefits of the bystander effect while minimizing potential toxicities to healthy tissues.

We are leveraging our expertise to advance platform innovations that further expand the potential of our ADCs to deliver clinically meaningful benefit for cancer patients. Our areas of focus include the development of alternative scaffolds to increase homogeneity of our ADCs, alternative payloads to address additional indications and drug resistance and alternative targeting moieties to improve tumor penetration and biodistribution.