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MabPlex’s Manufactured Monoclonal Antibody Receives IND Approval from the U.S. Food and Drug Administration

Leading Contract Development and Manufacturing Organization (CDMO) MabPlex International, serving the global biopharmaceutical and biotechnology industries with sites in China and the United States, confirmed that an Investigational New Drug (IND) application has been approved by the U.S. Food and Drug Administration (FDA) for one of the company’s undisclosed customer’s proprietary antibody drugs.

The IND program is the means by which a pharmaceutical company obtains permission to start human clinical trials and to ship an experimental drug across state lines, within the United States, to clinical investigators  before a marketing application for the drug has been approved.

Comprehensive appraoch
MabPlex, which offers comprehensive (cell line) development, process characterization, conjugation optimization, cGMP manufacturing, and aseptic fill finish solutions for monoclonal antibody (mAb) and antibody-drug conjugate (ADC) therapeutics, was contracted to develop and manufacture the product from cell line development to IND filing in both the United States and China.

MabPlex’s high standards in development and cGMP quality management have been recognized by regulators in the United States, Australia and China, demonstrating the strength of the company’s global CDMO services…

For this project, MabPlex provided fully integrated services from cell line development to final drug product including a complete CMC package in support of the United States IND submission. Additionally, MabPlex will assist in completing the IND filing for the Chinese NMPA in the near future.

“This approval adds another milestone to our global repertoire of international IND submissions after the successful approval of an Australian IND last year,” noted Jianmin Fang, Ph.D, Chairman and Chief Executive Officer of MabPlex International.

“MabPlex’s high standards in development and cGMP quality management have been recognized by US, Australian and Chinese regulators demonstrating the strength of our global CDMO services,” Fang added.

Founded in 2013, MabPlex currently has two sites in China (Yantai and Shanghai) and one site in the United States (San Diego, CA).

Last Editorial Review: January 17, 2019

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Engineering Bispecific Antibodies to Cross the Blood-brain Barrier

Over the past decades, the development and regulatory approval of antibody-based therapeutics has progressed rapidly. But poor blood-brain barrier permeability has hampered the progress of effective antibody therapies for conditions in which the target is located in the central nervous system or CNS, which includes the brain.

One reason for this delayed progress is that the blood-brain barrier is a dynamic filtering mechanism that separates the brain from the circulatory system that carries blood to the brain and spinal cord tissue.

A complex interplay
The blood-brain barrier is formed from highly specialized endothelial cells that line the brain capillaries. Its structure and function dependent on the complex interplay between endothelial cells, astrocytes and pericytes, within the extracellular matrix of the brain and with the blood flow in the capillaries.

While the blood-brain barrier ensuring the passage of oxygen, carbon dioxide and glucose it blocks the passage of compounds including drug molecules designed to treat human disease, as well as proteins and cells.

Danica Stanimirovic, Kristin Kemmerich,  Arsalan Haqqani, Graham Farrington, researchers from the Human Health Therapeutics Portfolio, National Research Council of Canada, Ottawa, Ontario, Canada and Biogen Idec Inc., Cambridge, Massachusetts, USA, found that increased brain penetration of therapeutic antibodies can be achieved by engineering bispecific antibodies in which one antibody binding specificity recognizes a blood-brain barrier receptor that undergoes receptor-mediated transcytosis from the circulatory compartment into brain parenchyma, and the second binding specificity recognizes a therapeutic target within the central nervous system.

Bispecific antibodies are unique in a sense that they combine two or more antigen-recognizing elements into a single construct, which allows them to bind to two or more targets.

Antibody fragments
These bispecific antibodies can be built using various antibody fragments as “building blocks,” including monomeric single-domain antibodies, the smallest antigen-binding fragments of immunoglobulins. The development of blood-brain barrier -crossing bispecific antibodies requires targeted antibody engineering to optimize multiple characteristics of ” blood-brain barrier carrier” and therapeutic arms, as well as other antibody properties impacting pharmacokinetics and effector function.

Bispecific antibodies
Over the years, several blood-brain barrier-crossing bispecific antibodies have been developed using transferrin receptor antibodies as blood-brain barrier carriers. However, the principal obstacle for capitalizing on this future promise of central nervous system -active antibodies remains the scarcity of known, characterized receptor-mediated transcytosis receptors which could be exploited for the development of blood-brain barrier carriers.

In Advances in Pharmacology; Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders, volume 71, 2014, Stanimirovic  and her team review the recent advances and guiding principles for designing, engineering, and evaluating blood-brain barrier-crossing bispecific antibodies. The authors also discusses approaches to identify and characterize novel blood-brain barrier-crossing antibodies and receptor-mediated transcytosis receptors. [1]

In an unrelated study the researchers demonstrates that modular incorporation of the blood-brain barrier permeable single-domain antibody FC5 in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for central nervous system indications. [2]


Danish Researchers Develop New Method for Efficient Tagging of Proteins

Researchers at the Aarhus University, Denmark’s second oldest university, have developed an easier method to create DNA–protein conjugates. The method can potentially strengthen the work involved in diagnosing diseases. Their findings are published in the July online edition of Nature Chemistry [1]

DNA linked to proteins, including antibodies, provides a strong partnership that can be used in diagnostic techniques, nanotechnology and other disciplines. DNA–protein conjugates, which tag proteins with DNA, can be used for the sensitive detection and visualisation of biological material. The method also provides easier access to handling proteins in nanotechnology, where the DNA acts as a handle on the protein.

A real challenge
Controlling the conjugation of macromolecules such as DNA and proteins can be quite a challenge when scientists want to join them in particular ways and places. Researchers at Aarhus University have now developed a new and efficient method to tag proteins with DNA, making it much simpler to control the process than previously. The new method was developed at the Danish National Research Foundation’s Centre for DNA Nanotechnology… in collaboration between researchers atAarhus University’s Interdisciplinary Nanoscience Centre (iNANO), Department of Chemistry and Department of Molecular Biology and Genetics.

“Maintaining the protein’s function and activity often requires the attachment of only a single DNA strand to the protein. At the same time, it can be important to know where the DNA strand is attached to the protein. You can normally only achieve this if you are working with genetically engineered proteins. This is a time-consuming and technically challenging process,” explains PhD student Christian B. Rosen, CDNA, Aarhus University – one of the researchers behind the new method.

Direct Tagging
The new method makes it possible to direct the tagging of proteins with DNA to a particular site on the protein, without genetically modifying the protein beforehand. In other words, it is possible to tag natural proteins, including antibodies.

The researchers use a piece of DNA that is engineered to bind to metal ions. Using this ‘control stick’, they direct another piece of DNA to a metal binding site on the protein, where it reacts. A considerable number of proteins bind metal ions, which makes them suitable for this method. A significant point in using this method is that the tagged proteins retain their functionality after being bound to DNA.

The researchers are applying for a patent for the new method, which has potential in a number of areas. The technique called DNA-templated protein conjugation, facilitates the production of site-selective protein conjugates, and also conjugation to IgG1 antibodies via a histidine cluster in the constant domain.

“Of greatest importance is the fact that we can use our technique for tagging antibodies. Antibodies that are chemically bound or conjugated to chemotherapeutics represent an entirely new class of medicine called antibody-drug conjugates or ADCs, in which the antibody part is used to recognize specific tissue and the chemotherapeutic part is used to kill the cell. [2] When you tag antibodies, it’s important that you keep the recognition element of the antibody intact. With our method, we strike the constant part of the antibody and not the variable part, which contains its recognition element. Our technique is therefore general for a major class of proteins,” noted Anne Louise Bank Kodal, CDNA, another author of the article.

The researchers are working on further developing the method so they can attach chemotherapeutics to antibodies and not just DNA.


Toxicology Study Demonstrates Decreased Mortality and Better Tolerability of ADC Generated with SMARTag Platform vs. Conventional Technology

Results of an in vivo toxicology study, demonstrates that an Antibody Drug Conjugate or ADC generated using the proprietary SMARTag™ platform has a better toxicity profile than a conventional ADC. The study, conducted in a rat model by scientists at Redwood Bioscience, Inc.(Emeryville, CA), a company developing precision protein-chemical engineering technology to produce next-generation antibody-drug conjugates and other semi-synthetic biotherapeutics, compared the effects of a single dose of 6, 20 or 60 mg/kg of a SMARTag ADC conjugated to a cytotoxic payload using the proprietary HIPS chemistry, to an ADC generated with traditional conjugation methods.

The researchers found that the SMARTag ADC was well tolerated and provided statistically significant survival benefits versus the conventional ADC, particularly at high doses where the conventional ADC resulted in mortality. Elevations in liver enzymes and decreases in platelet counts and reticulocytes were also observed with the conventional ADC at 20 and 60mg/kg treatments, whereas these effects were only seen with the highest dose of the SMARTag ADC. In addition the toxicokinetic analysis showed that the SMARTag ADC had greater exposure and longer circulating half-life than the conventional ADC comparator.

SMARTag™ platform
Redwood’s proprietary SMARTag site-specific protein modification and cytotoxin-linker technologies enable the generation of homogenous bioconjugates engineered to enhance potency, safety and stability. The technology employs natural post translational modifications found in human cells to site specifically create one or more aldehyde tags on protein molecules. These chemical handles are then stably conjugated to cytotoxic payloads to prevent their systemic release. The SMARTag platform provides precise payload positioning and defined stoichiometry of payload–protein ratios. The control afforded by the technology enables identification of superior drugs from libraries of differentially designed conjugates.

This unique chemistry results in a stable C-C bond between the antibody and the cytotoxin payload. In comparisson to other linker chemistries, this creates a uniquely stable connection.

The site-specific payload placement – using SMARTag – allows for control over both the drug-to-antibody ratio or DAR and the site of conjugation. Both play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of an ADC. In addition, linker composition also plays an important role in the properties of an ADC.

David Rabuka, PhD, Founder and President and Chief Scientific Officer of Redwood Bioscience, noted: “In summary, the study showed that the SMARTag ADC was a less toxic treatment and, taken together with the efficacy studies, points to an improved therapeutic index for the SMARTag ADC compared to the conventionally conjugated ADC.”

“This data provides further evidence of the potential benefits the SMARTag technology offers our customers developing next-generation ADC therapies, and their patients,” added Barry Littlejohns, President, Advanced Delivery Technologies, Catalent Pharma Solutions (Somerset, NJ).


Results from Phase I Trial with SGN-CD19A Shows Encouraging Anti-tumor Activity in Non-Hodgkin Lymphoma

Results from an interim phase I clinical trial presented at the 50th Annual Meeting of the American Association of Clinical Oncology (ASCO), being held May 30 – June 3, 2014 in Chicago, Ill, shows that SGN-CD19A (Seattle Genetics, Inc, Bothell, WA 98021, USA), an antibody-drug conjugate or ADC in development for the treatment of B-cell malignancies, offers encouraging anti-tumore activity in patients with Non-Hodgkin Lymphoma (NHL).[1]

Lymphoma is a hematological (blood) cancer that begins in cells of the immune system. The two main forms of lymphoma are Hodgkin lymphoma (HL), which is marked by the presence of a type of cell called the Reed-Sternberg cell, and non-Hodgkin lymphoma (NHL). Lymphoma occurs when lymphocytes, a type of white blood cell, grow and multiply uncontrollably. When unchecked, these cancerous lymphocytes travel to various parts of the body, including the lymph-nodes, spleen, bone marrow, blood, or other organs, where they form tumors.

Diffuse large B-cell lymphoma or DLBCL is the most common form of NHL, accounting for up to 30% of newly diagnosed cases in the United States. DLBCL is an aggressive or fast-growing lymphoma and arises both in lymph nodes as well as outside of the lymphatic system, in the gastrointestinal tract, testes, thyroid, skin, breast, bone, or brain. Although DLBCL is the most common form of NHL, there are several other subtypes, including indolent (slow-growing) NHL that behave and respond to diferently to treatment.

Lymphoma, including HL and NHL, represents approximately 5% of all cancers in the United States. Based on data from the American Cancer Society,  nearly 70,000 new cases of NHL and 9,300 new cases of Hodgkin lymphoma are estimated for 2014.

…interim phase I data in aggressive non-Hodgkin lymphomas (NHL) along with previous phase I data in acute lymphoblastic leukemia (ALL), demonstrates that SGN-CD19A has encouraging antitumor activity with multiple complete remissions in a patient population with significant unmet needs…

Targeted Approach
The trial drug SGN-CD19A is an Antibody-drug Conjugate or ADC targeting CD19, a protein expressed on B-cell malignancies ALL and NHL, including DLBCL. Using Seattle Genetics’ proprietary technology, SGN-CD19A is comprised of an anti-CD19 monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin F or MMAF. An antibody-drug Conjugates is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into CD19-expressing tumor cells. In this process, ADCs harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the antitumor activity.

Preclinical data presented at the 2011 American Association for Cancer Research Annual Meeting demonstrated that SGN-CD19A effectively binds to target cells, internalizes and induces potent cell-killing activity and durable tumor regressions at low doses in multiple preclinical cancer models. SGN-CD19A is being evaluated in two ongoing phase I clinical trials for patients with B-cell ALL and aggressive NHL.

Study results
Data were reported from 37 patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL), including 32 patients with diffuse large B-cell lymphoma (DLBCL), four patients with mantle cell lymphoma (MCL) and one patient with Grade 3 follicular lymphoma. The median age of patients was 65 years and the median number of prior systemic therapies was two, with 10 patients (27%) having received a prior autologous stem cell transplant. Among enrolled patients, eight percent were primary refractory, 54% were refractory to their last treatment and 38% had relapsed following a response to their last treatment.

Primary Endpoints
The primary endpoints of the ongoing clinical trial are to estimate the maximum tolerated dose and to evaluate the safety of SGN-CD19A. In addition, the trial is evaluating antitumor activity, pharmacokinetics, progression-free survival and overall survival. In this dose-escalation study, patients receive a single dose of SGN-CD19A on an every 3-week basis. Key findings included:

  • No dose limiting toxicity was observed in the first cycle for any patients. Adverse events were observed in the 6 milligrams per kilogram (mg/kg) dosing regimen after the first cycle, therefore enrollment was discontinued. The 3, 4 and 5 mg/kg cohorts are being expanded, and the trial continues to enroll.
  • At the time of data analysis, of the 37 patients treated across all dose levels, the objective response rate observed was 30% (11 patients).
  • Six patients (16%) achieved a complete remission, five (14%) achieved a partial remission, 13 (35%) had stable disease and 13 (35 percent) had progressive disease as best response.

The clinical trial is ongoing with nine of the 37 patients (24%) remaining on treatment and new patients continuing to be enrolled.[2][3]

Adverse events
The most common adverse events of any grade occurring in more than 30 percent of patients were blurred vision (51%), fatigue (38%), dry eye (35%), constipation (30%) and keratopathy (30%). Grade 3 or higher adverse events observed in two or more patients included blurred vision (six patients), keratopathy (three patients), low platelet count (three patients) and anemia (three patients).

Final results
Commenting on the data, Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics, noted: “We continue to make strong progress advancing our proprietary pipeline programs, with SGN-CD19Autive Vice President, Research and Development at Seattle Genetics. The interim phase I data in aggressive non-Hodgkin lymphomas presented at ASCO, along with previous phase I data in acute lymphoblastic leukemia, demonstrate that SGN-CD19A has encouraging antitumor activity with multiple complete remissions in a patient population with significant unmet needs. The safety profile of SGN-CD19A is generally manageable with a notable absence of significant neuropathy or bone marrow suppression, which may enable future clinical trials with novel combination regimens. We look forward to final results from this ongoing phase I clinical trial to inform future SGN-CD19A program development plans.”


Study Confirms DMOT4039A Shows Anticancer Activity in Patients with Pancreatic or Ovarian Cancer

A study presented at the 50th Annual Meeting of the American Society for Clinical Oncology (ASCO) being held May 30 – June 3, 2014 in Chicago, Ill, describes the results of a phase I clinical trial of the investigational agent DMOT4039A (also known as RG7600; Genentech/Roche) against pancreatic and ovarian cancers. In this early clinical trial with the goal of identifying possible risks and defining likely dosages, the drug was well tolerated and in some patients showed initial evidence of anti-cancer activity.

According to data from the American Cancer Society, pancreatic cancer accounts for about 3% of all cancers in the U.S., and accounts for about 7% of cancer deaths. The ACS data further shows that about 46,420 people (23,530 men and 22,890 women) will be diagnosed with pancreatic cancer and about 39,590 people (20,170 men and 19,420 women) are expected to die as a result of the disease. [1]

Ovarian cancer risk
Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about 1 in 73. Her lifetime chance of dying from ovarian cancer is about 1 in 100. [2]

Ovarian cancer mainly develops in older women. About half of the women who are diagnosed with ovarian cancer are 63 years or older. The disease is more common in white women than African-American women. The ACS expected that in 2014 about 21,980 women will receive a new diagnosis of ovarian cancer and an estimated 14,270 women will die from the disease.[2]

Colin Weekes
Colin Weekes

New drug candidate
The investigational drug DMOT4039A* is a combination of a chemotherapeutic agent with an antibody, technically called an antibody-drug conjugate or ADC. Just as cells of the immune system use antibodies to recognize pathogens, researchers in this study designed antibodies to recognize a protein over-expressed by these cancer cells. In this case, the protein is mesothelin. The engineered antibodies attach to mesothelin on the cells, and bring along their chemotherapeutic cargo directly to the mesothelin-rich cancer cells.[3]

“The deal is that the cell has to express the protein. The more it’s expressed only on cancer cells, the more targeted the therapy becomes,” explained Colin Weekes, MD, PhD, (Photo) CU Cancer Center investigator and assistant professor in the Division of Oncology at the CU School of Medicine.

From T-DM1 to Kadcyla
A similar antibody-drug conjugate approach is used by the breast cancer agent T-DM1 (Trastuzumab emtansine, Kadcyla®, Genentech/Roche), which attaches chemotherapy to an antibody that seeks the HER2 protein in HER2+ breast cancers.

The current phase I clinical trial, sponsored by the agent’s manufacturer, Genentech, was carried out at the University of Colorado Cancer Center, in the Netherlands, and at three Mayo Clinic locations in Scottsdale, Arizona, Jacksonville, Florida, and Rochester Minnesota. The study enrolled 71 patients, with no dose-limiting toxicities seen at maximum study dosage.[4]

Does it make sense?
“For tumors that overexpress a specific protein ADCs may make sense,” Weekes says. “But for other tumors with specific genetic abnormality that doesn’t result in overexpression of a protein, it won’t make sense.” Weekes further explained that the creation of antibody-drug conjugates requires technically sophisticated procedures to create “linker constructs” between drug and antibody. “You can’t just put any drug on these things,” Weekes says.

But in tumors that overexpress certain proteins, or perhaps in tumors that can be made to overexpress certain proteins, the strategy of targeting cancers with antibody-drug conjugates remains promising. The agent DMOT4039A is now being evaluated for further human clinical trials.

* DMOT4039A  (also known as RG-7600) is an Antibody-drug Conjugate in which a humanized IgG1 anti-MSLN monoclonal antibody is conjugated to the cytotoxic agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linker.

Last Editorial Review: March 7, 2015


Phase II PRECEDENT Trial of Vintafolide in Platinum-Resistant Ovarian Cancer Basis for Regulatory Application

Based on trial results from the randomized Phase II PRECEDENT trial for vintafolide (MK-8109/EC145; Merck and Endocyte), an investigational folate small molecule drug conjugate or SMDC, published in the Journal of Clinical Oncology (JCO), the official journal of the American Society of Clinical Oncology, a regulatory application is currently under review with the European Medicines Agency for the treatment of folate-receptor positive platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin (PLD). Enrollment is ongoing in the pivotal Phase III PROCEED clinical trial with vintafolide, along with investigational companion imaging agent etarfolatide (EC20), in platinum-resistant ovarian cancer.

As reported in the online edition of the October 14, 2013 edition of JCO online, results from the Phase II PRECEDENT trial showed that administration of vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in women with platinum-resistant ovarian cancer resulted in a median progression-free survival (PFS) of 5.0 months compared to 2.7 months for those treated with PLD alone (HR=0.63; 95% CI 0.41–0.96; p=0.031) in the intent-to-treat (ITT) population. Those patients shown to have folate receptor-positive tumors, as defined by all selected target lesions being folate receptor-positive (FR%100) using the investigational folate receptor-targeted companion diagnostic imaging agent etarfolatide, demonstrated greater benefit, as measured by PFS, from treatment with vintafolide plus PLD versus PLD alone. Median PFS benefit in these patients was 5.5 months compared to 1.5 months for PLD alone (HR=0.38; 95% CI 0.17–0.85; p=0.013).

Folate Receptor-Positive Platinum-Resistant Ovarian Cancer
In 2013, it is estimated that there will be 22,240 new cases of ovarian cancer in the United States and over 40,000 new cases in the European Union. Ovarian cancer is one of the most lethal cancers of the female reproductive system. Overall, approximately 80 percent of patients relapse after first-line platinum-based chemotherapy. Platinum-resistant ovarian cancer is a challenging disease with a high unmet need. This type of cancer recurs within six months of completion with a platinum-containing regimen, the standard of care for ovarian cancer. Based on the Phase II PRECEDENT trial data, an estimated 80 percent of platinum-resistant ovarian cancer patients have been found to have folate receptor-positive disease as assessed by etarfolatide scanning, and approximately 40 percent express the receptor, as detected by etarfolatide, in all of their target tumor lesions.

A promising strategy
Etarfolatide is being developed by Endocyte as a non-invasive method to identify tumors that express the folate receptor. “The combination of vintafolide plus PLD demonstrated significant improvement in progression-free survival over standard treatment in women with folate receptor-positive platinum-resistant ovarian cancer,” said R. Wendel Naumann, M.D., Associate Director, Gynecologic Oncology, Carolinas HealthCare System’s Levine Cancer Institute, Charlotte, N.C., and corresponding author of the publication. “Targeting the folate receptor, which is expressed on the majority of epithelial ovarian cancers, is a potentially promising strategy, especially when combined with a companion diagnostic that is designed to identify patients who are most likely to respond to the treatment, a hallmark of personalized medicine.”

The Phase II PRECEDENT trial was an international, multi-center, randomized study of 149 women with platinum-resistant ovarian cancer. Patients were randomized to receive vintafolide plus PLD or PLD alone at a standard dose, until disease progression or death. The primary endpoint of the study was PFS. Secondary endpoints included response rate and overall survival (OS). In the ITT population, no difference was observed in overall survival (HR=1.010; 95% CI 0.679–1.503; p=0.957). Endocyte first presented results from the Phase II PRECEDENT trial at the 2011 American Society of Clinical Oncology Annual Meeting.

Well Tolerated
Vintafolide is an investigational proprietary, injectable, folate SMDC consisting of folate (vitamin B9) linked to a potent vinca alkaloid chemotherapy agent, desacetylvinblastine hydrazide (DAVLBH). Vintafolide is designed to target the chemotherapy agent to rapidly growing cancer cells that actively take up folate via the folate receptor. The folate receptor is expressed in a wide variety of cancers including ovarian cancer.

The combination of vintafolide and PLD was generally well tolerated, and no drug-related mortality or statistically significant difference in the incidence of drug-related serious treatment-emergent adverse events (TEAEs) was observed:

  • In the vintafolide and PLD arm vs. PLD arm, anemia, neutropenia and thrombocytopenia were reported in 16.6% vs. 10.4%, 19.1% vs. 10.4%, and 2.7% vs. 3.0% of all cycles, respectively.
  • Stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome) occurred in 16.6% vs. 22.8%, and 19.1% vs.15.8% of cycles, respectively.
  • The frequency of fatigue was similar between arms, 15.8% of vintafolide and PLD arm cycles, and 14.9% of PLD arm cycles.

Companion diagnostics
Etarfolatide (EC20) is an investigational folate receptor-targeted companion diagnostic imaging agent that is being developed as a non-invasive method to identify tumors that express the folate receptor. These tumors are the molecular target of Endocyte’s folate receptor-targeted therapeutic compounds such as vintafolide. Folic acid is used with etarfolatide for the enhancement of image quality. Etarfolatide is under review with the EMA and has been granted orphan drug status by the European Commission.

Ongoing Clinical trials
Vintafolide in combination with PLD is currently under review with European Medicines Agency (EMA) for the treatment of adult patients with folate receptor-positive platinum-resistant ovarian cancer. Vintafolide has also been granted orphan drug status by the European Commission. Vintafolide, along with investigational companion imaging agent etarfolatide, is currently being evaluated in a Phase III PROCEED clinical trial for platinum-resistant ovarian cancer and a Phase IIb TARGET trial for non-small cell lung cancer (NSCLC). A Phase II randomized trial of vintafolide in folate receptor-positive triple negative breast cancer is expected to be initiated in the near future.


Phase I Trial of SGN-LIV1A Initiated in LIV-1-Positive Metastatic Breast Cancer

A new phase I clinical trial was initiated late October 2013 to evaluate SGN-LIV1A in patients with LIV-1-positive metastatic breast cancer. SGN-LIV1A is based on Seattle Genetics’ antibody-drug conjugate (ADC) technology. The trial is designed to assess the safety and antitumor activity of SGN-LIV1A, an ADC targeted to zinc transporter LIV-1 (SLC39A6 or ZIP6), an estrogen regulated protein which is expressed in most subtypes of metastatic breast cancer.*  [1][2]

In the United States, breast cancer is the most commonly diagnosed cancer in women and one in eight women will be diagnosed with breast cancer in their lifetime. Breast cancer is the second leading cause of death among women. The American Cancer Society estimates that over 230,000 new cases of invasive breast cancer will be diagnosed in the United States during 2013, and approximately 40,000 people will die from the disease.

Treatment of cancer is changing with the introduction of more targeted agents and understanding disease-specific prognostic factors. Antibody-drug conjugates are an example of this evolving landscape…

SGN-LIV1A is an antibody-drug conjugate comprised of an anti-LIV-1 monoclonal antibody linked to a synthetic cytotoxic cell-killing agent, monomethyl auristatin E (MMAE). The trial drug is designed to be stable in the bloodstream, and to release its cytotoxic agent upon internalization into LIV-1-expressing tumor cells, which is expressed in most subtypes of metastatic breast cancer. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing the anti-tumor activity.

“Antibody-drug Conjugates represent a novel treatment approach that have demonstrated activity in both hematologic and solid tumors. SGN-LIV1A is one of four ADCs that we are advancing into the clinic during 2013, demonstrating our significant investment in this approach for the treatment of cancer,” noted Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development, at Seattle Genetics. “The target expression in breast cancer, preclinical antitumor activity, and need for novel therapeutic options for advanced breast cancer patients all support the clinical evaluation of SGN-LIV1A,” he explained.

Targeting ability
ADCs are designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing anti-tumor activity.

New trial and primary endpoint
The study is a phase I, open-label, dose-escalation clinical trial to evaluate the safety and antitumor activity of SGN-LIV1A in patients with LIV-1-positive metastatic breast cancer and is enrolling patients with triple negative disease who have previously been treated with at least two prior cytotoxic regimens in the metastatic setting, or patients with ER-positive and/or PR-positive and HER2-negative disease who have previously been treated with at least two prior cytotoxic regimens in the metastatic setting, and at least three prior hormonal therapies. The primary endpoint of the trial is safety, with key secondary endpoints of objective response, duration of response and Progression-free Survival or PFS. The study is expected to enroll up to 70 patients at multiple centers in the United States.

“The treatment of cancer is changing with the introduction of more targeted agents and understanding disease-specific prognostic factors. Antibody-drug conjugates are an example of this evolving landscape, representing a rational approach to targeted drug delivery,” said Howard A. Burris, M.D., Chief Medical Officer, Executive Director of Drug Development at Sarah Cannon Research Institute and investigator for this phase I clinical trial. “We are eager to evaluate SGN-LIV1A in this phase I trial for advanced breast cancer.”

Preclinical data
At the annual meeting of the American Association of Cancer Research in April 2013, preclinical data demonstrated that up to 92% of breast tumors analyzed expressed LIV-1, with limited expression in normal tissue. SGN-LIV1A demonstrated significant anti-tumor activity in multiple preclinical models at well-tolerated doses. The preclinical in vitro data for SGN-LIV1A demonstrated target specific internalization and cytotoxic activity against a breast cancer cell line while in vivo studies demonstrated anti-tumor activity in preclinical xenograft models with significant delay of tumor growth compared to control groups. These findings support further evaluation and development of SGN-LIVA as a therapeutic for the treatment of metastatic breast cancer. [3]

LIV-1 is and present in increased amounts in estrogen receptor-positive breast cancer as well as in tumors that spread to the lymph nodes.

Photo Credit: Seattle Genetics


EORTC/GIMEA Trial Does Not Show Benefits for Older AML Patients

Results of a randomized phase III trial evaluating the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy provides no benefit in older patients with newly diagnosed acute myeloid leukemia (AML). The results of the EORTC/GIMEMA 06012 intergroup trial (AML-17) are published in the October 14, 2013 issue of the Journal of Clinical Oncology and also show that the combination is too toxic for patients 70 years of age or older. Gemtuzumab ozogamicin is an antibody-drug conjugate comprised of an anti-CD33 monoclonal antibody linked to a cytotoxic agent.

The study results show that patients younger than 70 years with secondary acute myeloid leukemia might possibly benefit from such treatment. However, outcomes were significantly worse in the oldest age subgroup due to a higher risk of early mortality.

An intensification strategy combining two upfront higher doses of gemtuzumab ozogamicin with sequential induction chemotherapy is highly myelosuppressive and not beneficial in older patients

Professor Sergio Amadori, M.D. of the Tor Vergata University Hospital in Rome and Coordinator of this study noted: “This large trial in older patients with AML is the third randomized study to assess the addition of GO to chemotherapy in elderly patients with AML. So, it is an important addition to the literature.”

Other studies
Unlike the two trials published so far, the French ALFA-0701, and UK NCRI AML16 trial, a higher dose of GO was used. Furthermore, GO in induction was given before standard induction chemotherapy. According to the researchers, this turns out to be an important difference in the study design. While, as shown by the former trials, the addition of low doses of GO to chemotherapy resulted in a survival benefit for older patients with better-risk disease, the AML17 study clearly indicates that an intensification strategy combining two upfront higher doses of GO with sequential induction chemotherapy is highly myelosuppressive and not beneficial in older patients, particularly in the oldest age cohort where induction response and survival rates are significantly compromised due to excess early mortality.

“On the basis of the available studies, there is plausible evidence that lower doses of GO as an adjunct to standard chemotherapy may offer better outcomes for these patients with limited alternatives,” Amadori explained.

Study design
The EORTC GIMEMA trial included 472 patients with newly diagnosed acute myeloid leukemia who were between the ages of 61 and 75 years. Patients were randomly assigned to gemtuzumab ozogamicin (GO), 236 patients, or No GO, 236 patients, arms. The GO arm received a course of gemtuzumab ozogamicin followed by induction chemotherapy with mitoxantrone/cytarabine/etoposide. The No GO arm received only induction chemotherapy. Patients in remission received two consolidation courses with or without gemtuzumab ozogamicin.

Overall response rate was comparable in the two arms: 45% in the GO arm and 49% in the No GO arm. At a median follow-up of 5.2 years, the median overall survival, the primary endpoint, was 7.1 months in the GO arm and 10 months in the No GO arm (hazard ratio [HR], 1.20; 95% CI, 0.99 to 1.45; P = 0.07). Other survival endpoints were similar in both arms. Grade 3/4 hematologic and liver toxicity were greater in the GO arm.


Photo Credit: American Society of Hematology


Investigational Drug MLN0264 May Provide New Treatment Option for Pancreatic Cancer Patients

Patients with pancreatic cancer may benefit from MLN0264, an investigational member of an emerging class of anticancer drugs called antibody-drug conjugates or ADCs. Preclinical results of MLN0264 were presented at the International Conference on Molecular Targets and Cancer Therapeutics, held in the Hynes Convention Center in Boston, Massachusetts, USA, October 19-23, 2013. The meeting is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organization for Research and Treatment of Cancer (EORTC).

Antibody-drug conjugates are a new type of targeted anticancer therapy, which use an antibody to deliver an attached drug directly to those cells that display the antibody’s target on their surfaces. This precision reduces the side effects of the attached drug compared with conventional systemic administration. Currently, there are two U.S. Food and Drug Administration-approved antibody-drug conjugates used for the treatment of certain cancers.

“Our investigational antibody-drug conjugate, MLN0264, is designed to selectively bring a highly potent cytotoxic payload to tumors that express the transmembrane cell surface receptor guanyl cyclase C or GCC,” explained Petter Veiby, global head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, Massachusetts, USA.

GCC is expressed by ~95% of primary and metastatic colorectal cancer (mCRC) tumors and MLN0264 has shown selective binding and antitumor activity in mouse xenograft models of mCRC expressing GCC. The investigational drug is currently being investigated in a phase I study in patients with advanced gastrointestinal malignancies.

GCC is also expressed in subsets of pancreatic cancers. Further to the findings in mCRC, the researchers investigated GCC expression in human pancreatic tumors and evaluated MLN0264 activity in mouse xenograft models of GCC-expressing human pancreatic cancer. “As result,” Veilby notes, “Our findings in preclinical pancreatic tumor models [also] support the testing of MLN0264 in combination with gemcitabine in patients with advanced pancreatic cancer.”

Unique drug delivery combination
MLN0264 consists of the highly toxic, microtubule-disrupting agent monomethyl auristatin E or MMAE attached to an fully human anti-GCC monoclonal antibody that recognizes GCC via a protease-cleavable linker, licensed from Seattle Genetics. When the antibody portion of the drug recognizes the protein GCC on tumor cells, the entire drug is taken up by the cells. Once inside the tumor cells, the linker that attaches MMAE to the antibody is severed, allowing the tumor cells to be exposed to the cytotoxic activity of MMAE.

Study Design
According to Veiby, at least 50% of the pancreatic tumors he and his colleagues have examined express some level of GCC. They, therefore, investigated the activity of MLN0264 in preclinical models of pancreatic cancer that mimicked the various patterns of GCC expression observed in patient biopsies.

GCC expression in multiple human pancreatic cancer samples including tissue microarrays (TMAs) was evaluated by immunohistochemistry (IHC). For in vivo studies, 7 mouse xenograft primary human tumor explant (PHTX) models of pancreatic cancer were developed, including tumor tissue from patients with wild-type and mutant KRAS. Animals were treated when the tumor reached ~230 mm3. In single-agent studies, animals were administered vehicle, MMAE 0.135 mg/kg once weekly (QW), or MLN0264 3.75 or 7.5 mg/kg QW. In combination studies, animals received vehicle, or MLN0264 7.5 mg/kg QW alone or in combination with gemcitabine 15 or 20 mg/kg twice weekly (BIW), or gemcitabine 15 mg/kg on days 1, 3 each week. Average tumor volume was determined at multiple time points following the start of treatment using vernier calipers.

The researchers found that MLN0264 markedly inhibited the growth of five of seven different human pancreatic tumors transplanted into mice. Further analysis in two of the preclinical models, one in which MLN0264 had significantly inhibited tumor growth and one in which it had little effect, showed that a combination of MLN0264 and the traditional chemotherapy agent gemcitabine caused greater tumor shrinkage than either drug alone.

In the GCC-expressing PHTX-249 mouse xenograft model (KRAS mutant G12), single-agent MLN0264 showed significant tumor growth inhibition (TGI) versus vehicle or free MMAE by day 21, with the 7.5 mg/kg dose significantly better than 3.75 mg/kg by day 20-22. Similarly, in the GCC-expressing PHTX-215 model (KRAS wild-type), MLN0264 7.5 mg/kg resulted in significantly greater TGI (79%) versus free MMAE or MLN0264 3.75 mg/kg by day 22, including some tumor regression. Across the 7 models (variable apical GCC expression; KRAS wild-type and mutant), TGI ranged from 24% (p=0.17) to 79% (p<0.001) with single-agent MLN0264. In the PHTX-249 model, MLN0264 7.5 mg/kg plus gemcitabine 15/20 mg/kg BIW or 15 mg/kg, days 1, 3, showed significantly greater TGI than either agent alone. At day 20-21, TGI was 46-47% for single-agent MLN0264, 66-79% for gemcitabine 15 mg/kg BIW and gemcitabine days 1, 3, and 84-88% for the respective combinations; 3 of 7 animals in the latter combination group had a smaller tumor volume at day 20 versus day 0 (TGI, 93%).

Strong results
These findings indicate that MLN0264 has antitumor activity as a single agent and in combination with gemcitabine in GCC-expressing pancreatic cancer xenograft models, and support clinical evaluation of MLN0264 in patients with pancreatic cancer. Data from additional models will be presented.

Based on these preclinical results, the researchers plan to investigate the activity of the combination of MLN0264 and gemcitabine in patients with GCC-expressing pancreatic cancer in a phase II study, which they hope will begin sometime in 2014. They are also evaluating the activity of MLN0264 in preclinical models of two other cancers known to frequently express GCC, metastatic colorectal cancer and gastric cancer.

For more information:
Zhang J, Gallery M, Wyant T, Stringer B, Manfredi M, Danaee H, Veiby P.
MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC), demonstrates antitumor activity alone and in combination with gemcitabine in human pancreatic cancer xenograft models expressing GCC.
Abstract Number: PR12/B194
Presenter: Petter Veiby


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