Earlier this month French pharmaceutical giant Sanofi-aventis acquired an exclusive world-wide license to one of Oxford BioTherapeutics’ internal preclinical antibody programs. Sanofi-aventis intends to use the licensed antibody, which is directed against a novel, proprietary target identified by Oxford BioTherapeutics’, to develop, manufacture and commercialize antibody-drug conjugate (also called immuno-conjugate) products for the treatment of cancer.

Under the terms of the agreement, Sanofi-Aventis agreed to pay Oxford BioTherapeutics an undisclosed upfront cash payment, milestone payments on the program, and royalties on the worldwide products sales and will receive additional performance milestones.

“This is the most advanced antibody licensing deal that OBT has signed to date and I am delighted that the target and antibody capabilities that we have built have been recognized by a world leading pharmaceutical company such as Sanofi-Aventis,” said Christian Rohlff, CEO of OBT. “Given their expertise and experience in cancer drug development, I am very pleased that a program from our broad preclinical pipeline will be developed by Sanofi-Aventis.”

The initiative integrates Oxford BioTherapeutics’ expertise in cancer target and antibody discovery with the in-house antibody development capabilities of Sanofi-Aventis. A key component of Oxford BioTherapeutics’ expertise in cancer target discovery is the company’s OGAP® proteomic database, which represents one of the world’s largest proprietary human cancer cell-surface protein repositories combined with highly relevant genomic and clinical information derived from human blood and cancer tissue studies.

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Ongoing Development
Targeted cancer therapies, such as monoclonal antibodies that bind only to cancer cell-specific antigens to induce an immunological response against the target cancer cell to block the growth and spread of cancer, have become an important part of anticancer drug development. The use of monoclonal antibodies (mAbs) in an ‘unlabeled’ or ‘naked’ form as a single anticancer agent is sub-optimal. As a result, many strategies are being investigated to enhance their function. Among the options is to conjugate mAbs with radioactive isotopes, chemotherapeutic agents, or toxins to create highly targeted agents.

Antibody−drug conjugates (ADCs) are monoclonal antibodies linked to a cytotoxic small molecule. The agents combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules, thereby taking advantage of the best characteristics of both components and forming effective therapeutic products that attack tumor cells in a highly targeted manner.

Benefits of Antibody−drug Conjugates
Many of the new developments in anti-cancer drug development combines the long established finding of conventional cytotoxic agents and the emergence of molecularly targeted therapeutics. [1]

Anti-neoplastic drugs like doxorubicin, daunomycin, vinca-alkaloids, and taxoids, have demonstrated their ability to kill cancer cells but generally with limited selectivity and high toxic effects on normal cells yielding marginal therapeutic indices.

‘Naked’ or ‘unlabeled’ monoclonal antibodies such as rituximab, trastuzumab, cetuximab, bevacizumab, panitumumab, alemtuzumab, and ofatumumab, on the other hand, have demonstrated therapeutic utility in malignancies but are often combined with small cytotoxic drugs to achieve significant clinical efficacy.

Trastuzumab Emtansine
Trastuzumab emtansine (trastuzumab-DM1), being developed by researchers at Genentech/Roche for the treatment of HER2+ metastatic breast cancer, is a tumor-activated prodrug resulting from the conjugation of the humanized anti-HER2 mAb trastuzumab, which has been used in the treatment of breast cancer for over 10 years, with ImmunoGen Inc’s cytotoxic and antimitotic maytansine derivative DM1. [2]

Maytansinoids are potent microtubule-targeted compounds that inhibit proliferation of cells at mitosis. While antibody-maytansinoid conjugates consisting of maytansinoids (DM1 and DM4) attached to tumor-specific antibodies have shown promising clinical results, the use as single agents is limited by toxicity. Conjugating DM1 with trastuzumab results in a compound that can deliver a cytotoxic agent directly to a targeted cell while reducing most safety concerns. Preclinical studies have reported that trastuzumab emtansine potentiates the effect of a number of chemotherapeutic agents such as carboplatin, 5-fluorouracil and docetaxel, offering an exciting option for the treatment of patients with refractory, metastatic breast cancer.[3]

In ongoing phase III trial Genentech/Roche continues to evaluate Trastuzumab emtansine for 2nd-line use. The randomized trial which began in February 2009 and compares T-DM1 – used as a single agent – to lapatinib (Tykerb®) plus capecitabine (Xeloda®). Overall survival (OS) has been added as a co-primary endpoint, and the sample size increased to 980. Application for marketing approval is expected in mid-2012 in the US and Europe.[4]

Another randomized phase III trial evaluating T-DM1 for 1st-line with the goal of applying for the marketing approval of T-DM1 for this application after 2013 in the US and Europe began in July 2010 and compares T-DM1 – used as a single agent – to trastuzumab plus docetaxel or paclitaxel. [5]

Not all Approaches Succeed
Despite technological advancement, not all antibody-drug conjugates ‘winners’. Gemtuzumab Ozogamicin (Mylotarg®, Wyeth/Pfizer), a combination of the antibody gemtuzumab and the chemotherapy ozogamicin (a calicheamicin analogue), was the only U.S.-approved antibody-drug conjugate available, before the manufacturer voluntarily removed it from the market. The drug had received accelerated approval in May 2000 to treat elderly patients with acute myeloid leukemia (AML) but failed to show clinical benefit (improved survival) in a required postmarketing studie combining the agent with chemotherapy. The fatal toxicity rate was higher in patients treated with gemtuzumab ozogamicin plus chemotherapy compared to patients treated with chemotherapy alone. This raised many new safety concerns. The agent was never approved by the European Medicines Agency.

Ongoing Projects
While Genetech and ImmunoGen are developing Trastuzumab emtansine, Sanofi-Aventis [6] and ImmunoGen are collaborating on other ADCs, including SAR3419, and consisting of an anti-CD19 monoclonal antibody conjugated and the maytansinoid DM4, a derivative of the cytotoxic agent maytansine (DM1). The Anti-CD19-DM4 conjugate SAR3419 targets the cell surface antigen CD19, found on a number of B-cell-derived cancers. Upon antibody/antigen binding and internalization, the Antibody−drug conjugates releases DM4, which binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of CD19-expressing tumor cells.

In preclinical xenograft models for non–Hodgkin’s lymphoma antitumor activity of SAR3419 showed that the compound was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. As a result of this and other preclinical trials Sanofi-Aventis initiated two Phase I trials with SAR3419. One of these trials is assessing the compound when dosed every three weeks and the other one is assessing a weekly dose.[7, 8].

A multi-dose-escalation safety and pharmacokinetic study was completed in 2010. [X] These trials have yielded impressive results, particularly in the weekly dosing study. As a result, sanofi-aventis has made the decision to advance SAR3419 into Phase II after obtaining some additional information in Phase I. Phase II testing is expected to start in 2011.

Sanofi-Aventis and ImmunoGen are also working on the development SAR566658, another Antibody-drug conjugate, targeting the DS-6 epitope, which is found on breast, ovarian, cervical, pancreatic cancers and on other solid tumors. So far, preclinical results presented during the 22nd EORTC-NCI-AACR symposium on “Molecular targets and Cancer Therapeutics” in Berlin, Germany (16 – 19 November 2010) are encouraging (Abstract #ENA-0184).

More Antibody-drug conjugates
ImmunoGen’s most advanced Tumor-Activated Prodrug (TAP) compound, lorvotuzumab mertansine (IMGN901) is an antibody-drug conjugate composed of a CD56-targeting antibody with the maytansinoid DM1. Cancer that express CD56 include solid tumors, such as small-cell lung cancer (SCLC), Merkel cell carcinoma (MCC), ovarian cancer, carcinoid, and other neuroendocrine tumors. They also include multiple myeloma (MM) and certain other types of liquid cancers.

The first part of the trial, which tested different doses of the compound to establish its maximum tolerated dose, has been completed and encouraging interim data were reported at the annual ESMO meeting in October 2010. The second part of the trial is currently recruiting participants.

Exciting Progress
Positive and exciting data from a pivotal trial Brentuximab Vedotin (SGN-35) have recently been published by Seattle Genetics Inc. and Millennium: The Takeda Oncology Company Brentuximab vedotin is targeted to CD30, a defining marker of Hodgkin lymphoma, and a target also expressed on various T-cell cancers and other hematologic malignancies. It is comprised of an anti-CD30 monoclonal antibody linked to monomethyl auristatin E (MMAE). The ADC uses a novel linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. The two companies coaborating in the development and commercialization of Brentuximab Vedotin plan to submit a Biologics License Application (BLA) in the first quarter of 2011, seeking approval for both relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.

Complex Development
A number of Antibody−drug conjugates, such as trastuzumab emtansine, inotuzumab ozogamicin, and brentuximab vedotin, have reached late clinical development stages and shown encouraging therapeutic effects against both solid tumors and hematological malignancies. Today, at least fifteen promising new ADCs are being investigated in clinical trials including glembatumumab vedotin and lorvotuzumab mertansine.[Reichert]

While complex, recent encouraging successes in the development of Antibody−drug conjugate and the potential approval around the corner, are slowly leading to new ways in the treatment of a great variety of cancers, bringing hope to many patients.

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