Basel, 19 April 2011
Diversity of approaches in research continues to empower scientific excellence at Roche
Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that the Group’s strong scientific publication track record from Genentech’s and Roche’s Research and Early Development units gRED and pRED continues. In 2010, Roche and Genentech researchers published several hundred scientific publications, including 18 of them in Nature, Science, or Cell. During the first three months of 2011, close to 100 scientific publications were published, two of them in Nature and Cell. In the future, Roche intends to provide regular updates on important scientific publications.
In a recent issue of Nature1, Genentech scientists published results elucidating a pathway by which tumors evade cellular response to antimitotic chemotherapy. Common chemotherapy regimens to treat frequent cancers including ovarian, breast or lung cancer today involve antimitotic agents such as paclitaxel and vincristine. By disrupting mitosis, the division of cells is inhibited, which specifically affects rapidly proliferating tumor cells. The pathway identified in the paper provides a molecular mechanism to explain why cells die in response to anti-mitotic chemotherapy.
“It is common for chemotherapy agents to stop working. Understanding resistance and trying to find a way around it is something that has occupied researchers for decades," Richard Scheller, Ph.D., Global Head Genentech Research and Early Development said.
gRED scientist Ingrid Wertz and colleagues now discovered that two proteins involved in mitosis , FBW7 and Mcl-1, are key components of a pathway that may determine whether antimitotic chemotherapy works or not. In cells that respond to paclitaxel, the tumor suppressor protein FBW7 induces a process called apoptosis, the biological suicide process by which abnormally behaving cells such as cancer cells self-destruct. When FBW7 is inactivated, the signaling pathway to control a second protein called Mcl-1 is disturbed. Mcl-1 is a protein that inhibits apoptosis. Resistance to anti-mitotic chemotherapy was therefore associated with high levels of Mcl-1 and inactivated FBW7. Determining the FBW7 and Mcl–1 status of tumors could identify patients that may not respond well to antimitotic chemotherapy before the decision on a treatment regimen is made.
“By shedding new light on an unanswered question about chemotherapy drug resistance, this work suggests a number of leads for diagnostics and also reveals targets for novel medicines to circumvent this resistance mechanism of cancer cells,” Richard Scheller concluded.
The March 28, 2011 online edition of Blood2 featured a publication by pRED scientists on GA101/RG7159, a type II, glyco-engineered and humanized antibody targeting the CD20 antigen on human B-cells. In this paper, Gerhard Niederfellner, Christian Klein and colleagues provide novel insight into the structural basis of the fundamentally different mechanisms employed by type II antibodies such as GA101 versus type I antibodies such as rituximab (MabThera/Rituxan) or ofatumumab in destroying malignant B cells. By crystallizing a fragment of GA101 in complex with a CD20 peptide, they determined the first three-dimensional structure of a type II CD20 antibody.
“CD20 is an important target for the treatment of B-cell malignancies. CD20 is also the target of Mabthera/Rituxan, a well-established Roche product approved for the treatment of NHL, CLL and rheumatoid arthritis,” Jean-Jacques Garaud, Global Head Roche Pharma Research & Early Development said. “The distinctive molecular basis for CD20 targeting by GA101, currently in late-stage development for hematological cancers, could explain its potentially higher efficacy compared to MabThera/Rituxan”.
The scientists discovered that GA101 binds CD20 in a completely different orientation compared to MabThera/Rituxan. Although the binding regions of both antibodies largely overlap, the core binding epitope for GA101 is shifted to the right and the binding axis is tilted. Moreover the so-called elbow angle of GA101 was found to be wider than that of MabThera/Rituxan. The elbow angle is the angle between the variable and constant antibody domains. It serves to increase flexibility thereby enhancing the antibody’s ability to simultaneously bind two ligands. The paper shows that the different spatial needs for CD20 binding by MabThera/Rituxan and GA101 cause each of the antibodies to recognize differently localized subpopulations of CD20 molecules on B cells. This distinct recognition is thought to be the molecular basis for the different mechanisms of type I and type II CD20 antibodies in attacking malignant B cells.
In addition to the type II related mode of action GA101 also shows enhanced antibody-dependent cellular cytotoxicity compared to MabThera/Rituxan. This is achieved through glyco-engineering of the antibody using the proprietary GlycoMAb technology, which allows GA101 to bind more tightly to immune effector cells such as natural killer cells. The clinical potential of GA101 to expand the therapeutic window and provide a more potent and efficacious treatment for patients is currently being studied in several phase II and phase III studies in both, indolent and diffuse large B-cell lymphoma as well as in chronic lymphocytic leukemia.
"We are pleased that through this research program and our continued focus on innovation, we may have the potential to offer a new option to treat patients with hematological malignancies”, said Jean-Jacques Garaud. “With its unique mode of action, we believe GA101 has the potential to extend the therapeutic benefit over MabThera/Rituxan in combination with chemotherapy as current standard of care, including treatment for patients who are refractory to current therapies."
Roche’s unique diversity of approaches for excellence in science
Roche believes that a diversity of views, cultures and approaches promotes creativity and innovation, especially in research and early development. To ensure a strong flow of suitable candidate molecules into its development pipeline, Roche has built a unique innovation network of independent research and development centres. Following the integration of Genentech, pRED and gRED operate as autonomous innovation centres focusing on new drug targets and new molecular entities (NMEs). They have their own budgets and external networks and take distinctive approaches to translating excellent science into meaningful advances in medical care. This organisational structure strengthens Roche Pharma’s ability to develop novel medicines and preserves the values and culture that enabled the Genentech success story.
Roche promotes a diversity of approaches in our pursuit of innovation. In addition to gRED and pRED, Roche Diagnostics and Chugai operate independently within the Group, forming the hubs of an innovation network that includes alliances with around 150 partners worldwide. Our Pharmaceuticals and Diagnostics Divisions have unparalleled expertise in molecular biology. Both divisions have industry-leading intellectual property and technology bases in this field, which they continue to strengthen through internal development and acquisitions. This expertise equips Roche to play a pioneering role in advancing personalised healthcare.
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiated medicines in oncology, virology, inflammation, metabolism and CNS. Roche is also the world leader in in-vitro diagnostics, tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostic tools that enable tangible improvements in the health, quality of life and survival of patients. In 2010, Roche had over 80’000 employees worldwide and invested over 9 billion Swiss francs in R&D. The Group posted sales of 47.5 billion Swiss francs. Genentech, United States, is a wholly owned member of the Roche Group. Roche has a majority stake in Chugai Pharmaceutical, Japan. For more information: www.roche.com.
1) Wertz et al., Nature, Volume: 471, Pages: 110–114, Date published: 03 March 2011:
Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7”
2) Niederfellner et al., Blood; published ahead of print March 28, 2011, doi:10.1182/blood-2010-09-305847
“Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies”
Research done in collaboration with: Gene Center, Dept. of Chemistry and Biochemistry, Ludwig-Maximilians University Munich
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