Over the last decade, antibody–drug conjugates or ADCs have emerged as powerful tool for the treatment of patients with cancer and hematological disorders.  These new drug combine the potency of cytotoxic molecules with the selectivity of antibodies targeted towards specific antigens exclusively present in cancer cells.

However, one of the most critical bottlenecks in the development of new antibody-drug conjugates is the identification of potent molecules – or cytotoxic payloads.  Marine compounds have shown interesting opportunities because they may possess the specific requirements needed to be considered to be a potential promising payload. Scientists at PharmaMar, a biotechnology company based in Colmenar Viejo (Madrid), Spain, have synthesized  a new polyketide isolated from the Madagascan sponge Lithoplocamia lithistoides.  The compound called PM050489 shows antimitotic properties in human tumor cells lines at subnanomolar concentrations and displays a distinct inhibition mechanism on microtubules assembly through a novel mode of action.

Photo: Carmen Cuevas, Ph.D, Research & Development Director, responsible for the R&D Department at PharmaMar including the areas of Drug Discovery, Medicinal Chemistry and Preclinical. Photo Courtesy: PharmaMar/Grupo Zeltia SA.

A poster presented at the 26th EORTC-NCI-AACR symposium, being held November 18 – 21, 2014 in Barcelona, Spain, (Abstract #502, Nov, 21, 9:08 am) showed data on the potency and selectivity of MI130004, a new ADC conjugating trastuzumab with a PM050489. [1][2]

Development
In developing this new antibody-drug conjugate, PM050489 was modified to include a suitable linker containing a maleimide group to enable conjugation to Cys residues. Furthermore, conjugation to the monoclonal antibody trastuzumab was performed after reduction of the antibody with a phosphine reagent and the resulting conjugate called MI130004 was purified by size exclusion chromatography. [1]

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Antitumor effect
The purified trial drug was tested for its cytotoxic potential against selected cell lines with high (HCC-1954 and SKBR- 3) or null (MCF-7 and MBA-MD-231) HER2 expression. To evaluate MI130004 in vivo 5−7 weeks old SCID female mice were subcutaneously implanted with a suspension of 5×106 JIMT-1 cells in 100 ml of cell culture medium. Following, tumor (ca. 115mm3) bearing animals (N = 10/group) were randomly allocated to receive MI130004 (10 mg/kg) or appropriate, placebo induced, control treatments.

Treatments were administered weekly for 5 consecutive weeks. Antitumor effect was calculated using DT/DC (%), defined as a percentage of the change in tumor size for treated (T) and placebo (C) groups during the placebo-treated survival time (D). complete tumor regression or CR was defined when tumor volume <63mm3 for 2 or more consecutive measurements.

Initial trial results
The trial drug MI130004 showed a remarkable selectivity towards cell lines with high HER2 expression (IC50s 0.282 and 0.182 nM against HCC-1954 and SK-BR-3 cell lines respectively, while, at the same time, HER2 null cells were unaffected in the range of concentrations tested (up to 300 nM).

In vivo, MI130004 also demonstrated efficiency in causing an outstanding tumor reduction.  An initial review showed  complete regressions in most of the animals that received the treatment. Furthermore, MI130004 demonstrated selective and significant in vitro activity in HER2 overexpressing cell lines and significant in vivo antitumor activity in mice bearing JIMT-1 xenografts.   Based on these initial pre-clinical results, the scientists confirmed the remarkable potential of marine compounds for the design of new antibody-drug conjugates with therapeutic anticancer properties.

Commenting on these initially results, Carmen Cuevas, Ph.D, Director of R&D at PharmaMar who is spearheading the research projects noted: “We are very excited to present our new therapeutic approach for ADCs using marine compounds, as they are showing a promising therapeutic profile in animal models compared to standard treatment.”

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