Photo: Poster session during the Annual Meeting of the American Association for Cancer Research Annual Meeting, Sunday March 31, 2019. Photo by © AACR/Todd Buchanan 2019

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. [1][2]

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.

ADC Bio
Lonza
MabPlex
 

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. [3][4]

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.

Distinct payloads
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.[5]

Modular Scaffold
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 [6][7][8]

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.[2]

Reference
[1] 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
[2] 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
[3] Levengood MR, Zhang X, Hunter JH, Emmerton KK, Miyamoto JB, Lewis TS, Senter PD. Orthogonal Cysteine Protection Enables Homogeneous Multi-Drug Antibody-Drug Conjugates. Angew Chem Int Ed Engl. 2017 Jan 16;56(3):733-737. doi: 10.1002/anie.201608292. Epub 2016 Dec 14. [Pubmed][Article]
[4] Kumar A, Kinneer K, Masterson L, Ezeadi E, Howard P, Wu H, Gao C, Dimasi N. Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads. Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3617-3621. doi: 10.1016/j.bmcl.2018.10.043. Epub 2018 Oct 26.[Pubmed][Article]
[5] Palmer AC, Sorger PK Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy. Cell. 2017 Dec 14;171(7):1678-1691.e13. doi: 10.1016/j.cell.2017.11.009. [Pubmed][Article]
[6] Kozytska MV, Yurkovetskiy A, Yin M, Bodyak N, Conlon P, Du B, Stevenson C, Gumerov D, et al. Discovery of the novel, homogeneous payload platform Dolasynthen for Antibody-Drug Conjugates. EORTC-NCI-AACR Symposium, Nov 2018, abstract 272.
[7] Thomas JD, Yurkovetskiy A, Yin M, Bodyak N, Tang J, Protopopova M, Kelleher E, Jones B, Yang L, et al. Indole-BiarylPyrrolobenzodiazepines(I-BiPs): A Potent and Well-tolerated Class of DNA Mono-alkylating Payload for Antibody-Drug Conjugates (ADCs) EORTC-NCI-AACR Symposium, Nov 2018, abstract 173.
[8] Bodyak et al. Bodyak N, Yurkovetskiy A, Park PU, Gumerov DR, DeVit M, Yin M, Thomas JD, Qin L, Lowinger TB, Bergstrom DA, et al. Trastuzumab-Dolaflexin, a Highly Potent Fleximer-Based Antibody-Drug Conjugate, Demonstrates a Favorable Therapeutic Index in Exploratory Toxicology Studies in Multiple Species AACR Annual Meeting, Apr 2015, abstract 641
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