Clinical-stage bio-pharmaceutical company, Mersana Therapeutics, presented preclinical data from the company’s proprietary Dolasynthen platform and its modular Synthemer scaffold during the 2019 Annual Meeting of the American Association for Cancer Research (AACR) held March 29 – April 3, 2019 in Atlanta, GA. 
Antibody-drug conjugates (ADCs) consist of a tumor targeted antibody, a drug (payload) with specified mechanism of action, and the chemical framework for attaching them to each other.
By selective delivery of the payload to the tumor and not to normal tissues, ADCs can provide greater efficacy and tolerability than systemic chemotherapies, which can translate to longer duration of treatment and response.
Combining different cancer therapies may improve the probability and magnitude of therapeutic responses. In turn, this reduces the likelihood of acquired resistance in an individual patient.
While current antibody-drug conjugates are restricted to just one payload per antibody, co-delivery of multiple therapeutic agents with different anticancer mechanisms as part of one antibody-drug conjugate, called dual-payload ADCs (DP-ADCs), could potentially overcome drug resistance as well as generate additive or synergistic anticancer effects that may enhance the anti-tumor efficacy. 
Conceptually, these dual-payload ADCs could extend these advantages into combination therapy, which is standard-of-care in clinical oncology. Such an approach utilizes sequential unmasking of cysteine residues with orthogonal protection to enable site-specific conjugation of each drug. And because the approach utilizes conjugation to native antibody cysteine residues, it is widely applicable and enables high drug loading for improved ADC potency.
Researchers at Mersana engineered a dual-payload ADC that delivers two mechanistically distinct payloads to a single target cell.
To build a precision DP-ADC, the researchers leveraged Mersana’s proprietary Synthemer platform, which enabled them to chemically attach the payloads to a synthetic scaffold in a defined manner, and then to chemically attach the loaded scaffold to the antibody.
The company’s prototype DP-ADC combines Mersana’s proprietary cytotoxic aurastatin derivative, auristatin F hydroxypropylamide (AF-HPA) which binds to tubulin and inhibits microtubule polymerization, with a DNA mono alkylator (I-BiP).
The novel DP-ADC maintained antigen binding and exhibited potent cytotoxicity, and reearchers observed both of the expected mechanisms of action in the target cells.
Although AF-HPA and I-BiP did not exhibit synergy in cytotoxicity studies in cancer cell lines, their combination in a DP-ADC is expected to confer potential clinical benefit over either single-payload ADC across patient populations due to the concept of Independent Action.
Synthemer, Mersana’s novel, second-generation, proprietary AF-HPA synthetic payload platform with a defined, fully homogeneous structure, allows for flexibility and precise control of dual-payload ADCs. This enables tuning of the drug:antibody ratio (DAR): 2-8 Synthemer moieties per mAb, the creation of high DAR ADCs, incorporation of multiple payloads in a fixed ratio (e.g. 1:1, 2:1, 3:1), solubilizing group and linker group matched to each payload and site-specific or stochastic conjugation 
The data presented by Mersana’s research team showed a strong correlation between the structure of the payload platform and observed activity in vivo and allowed for further optimization of hydrophilic modifiers and other physico-chemical enhancing components. based on the available data the researchers consider that fully homogeneous Dolasynthen ADCs present attractive features that make them suitable for future development.
 An Antibody-Drug Conjugate Carrying a Microtubule Inhibitor and a DNA Alkylator Exerts Both Mechanisms of Action on Tumor Cells. Presented during the 2019 annual meeting of the American Association for Cancer Research (March 31, 2019, 1:00 p.m – 5 p.m), Session: PO.ET01.01 – Antibody-drug Conjugates: New Agents and Technologies, Abstract: #232 / 23
 Dolasynthen – A Novel, Homogeneous Auristatin F Hydroxypropyl Amide Antibody-Drug Conjugate Platform. Presented during the 2019 annual meeting of the Americam Association for Cancer Research (April 1, 2019, 3:05 p.m. – 3:20 p.m.), Session: MS.ET01.01 – Novel Therapeutic Agents and Screening Approaches, Abstract: #2687
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