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How Meaningful Will Changes Be to Ethical Guidelines Following Jose Baselga’s Fall?

In the aftermath of the fall of renowned breast cancer researcher Jose Baselga, MD, PhD, following revelations last month of his failure to disclose millions of dollars in payments from industry, I reached out to learn a little bit more about current institutional conflict of interest policies, especially in light of the current trend promoting academic-governmental-industry collaborations in research.

Although most peer-reviewed scientific journals have clearly stated guidelines requiring authors to disclose conflicts of interest, what conflict of interest policies did institutions have in place to govern the behavior of their researchers?

Series of Investigative Articles
Baselga’s case was reported in a series of articles written by reporters from the New York Times and ProPublica, a nonprofit investigative journalism organization.

The articles detailed a culture of self-serving standards that personally benefited a privileged few at Memorial Sloan Kettering Cancer Center, where Baselga served as physician-in-chief, until he resigned a week following publication of the first article in September.

Written by ProPublica senior editor Charles Ornstein, and Times staffer Katie Thomas, the articles reported on Baselga’s practice of not disclosing his financial interests in numerous peer-reviewed journals such as the New England Journal of Medicine, The Lancet, and Cancer Discovery, where Baselga still serves as one of two editors-in-chief.

Cancer Discovery is published by the American Association for Cancer Research, and
Baselga had served as AACR president from 2015-2016.

According to the Times, Baselga appeared to have violated societal conflict of interest rules during his tenure, and at research conferences, including AACR, had touted drugs that he had undisclosed financial interests in, despite less-than-glowing results reported at those same meetings.

The series reported that in addition to his $1.5 million annual salary from Sloan Kettering, Baselga had also received about $3.5 million in compensation from industry since 2013 including serving as a board member or advisor with Bristol-Myers Squibb, Roche, and Varian Medical Systems.

Subsequent articles noted claims of other ethical lapses at the New York cancer center including a questionable financial arrangement between Sloan Kettering and an artificial intelligence start-up company, Paige.AI.

Following the public exposure, Baselga stepped down from his corporate boards, and MSKCC president Craig B. Thompson, MD, resigned from his board positions with Merck and Charles River Laboratories.

Responses to the matter also appeared in two Times’s Opinion pieces by former New England Journal of Medicine editor Marcia Angell, MD, on September 14 2018, on “Transparency Hasn’t Stopped Drug Companies From Corrupting Medical Research,” and by the Times’s editorial board about “Medicine’s Financial Contamination” on September 24, 2018

On October 5 2018, an opinion piece by a MSKCC patient and active volunteer Steven Petrow appeared in STAT. Its title: “Memorial Sloan Kettering, You’ve Betrayed My Trust.”

AACR Still Deliberating Baselga’s Editorial Status
Although reports made it clear that Baselga no longer had any affiliation with Sloan Kettering, I contacted AACR about scheduling an interview with an AACR official to discuss the association’s actions regarding Baselga’s papers as well as his status as co-editor-in-chief of Cancer Discovery.

AACR replied that it would issue a statement, and after undergoing internal review over several days, the association emailed the following:

“We have been working with Dr. Baselga to issue updates of his disclosures as they relate to articles published in AACR scientific journals. Dr. Baselga has identified and submitted the information required to update the published record for two articles in Cancer Discovery and three articles in Clinical Cancer Research. These corrections will publish in the next month’s issues of these two journals.

The AACR is convening a panel of experts, including physicians, basic scientists, a patient advocate, and other relevant individuals, to evaluate Dr. Baselga’s case with the goal of making a fact-based decision regarding the status of his leadership role as one of the Editors-in-Chief of Cancer Discovery.

Also, the AACR is currently reviewing its Conflict of Interest Guidelines and will make any necessary updates or revisions at the conclusion of the panel’s comprehensive evaluation.”

Role Model for Avoiding Conflicts of Interest
For additional insight into institutional conflict of interest policies, I called a colleague, Thomas Tachovsky, PhD, who had served as a technology licensing officer at the Massachusetts Institute of Technology.

Tachovsky did not comment specifically about the MSKCC situation, but reflected about his experience at MIT, noting that the predominantly engineering school had a culture of finding solutions to problems.

He said that MIT was very serious about doing things the right way, protective of its image, and scrupulous in evaluating relationships between the institution and outside organizations or companies.

In general, he added, much of society seems to have lost its moral compass today, making it especially important to handle mistakes head on rather than by applying implemental band-aids.

Tachovsky referred me to his colleague, Rupinder Grewal, MIT’s conflict of interest officer, who was hired to lead the newly formed CoI-dedicated office in 2012 in response to revised federal policy on conflicts of interest related to grant recipients.

Grewal explained that the U.S. Department of Health and Human Services revised its Public Health Service regulations on financial conflicts of interests in research in 2011.

The changes went into effect in August 2012 and shifted responsibility for determining relatedness of outside activities to MIT research from the individual to the institution.

“Until the new regulation, it was left up to individual researchers to determine if an outside relationship posed a potential conflict to their funded research.

“After 2012,” she continued, “the most profound change was that now the institution was responsible for making the determination of relatedness of a discloser’s significant financial interests [SFI] to their research and the process involved asking researchers for relationship details at the point that an SFI was disclosed.”

She noted that at MIT it was the responsibility of the researcher to disclose details about whether outside consulting did or did not impact his or her MIT research.

“MIT also has two parallel systems. Conflict of interest is a measure of money that’s triggered by established financial thresholds stated in MIT’s financial conflict-of-interest policy, and is reported on an ongoing basis. OPA, or outside professional activities, is a measure of time that is spent away from institutional activities that is reported annually.”

There is a two-step COI disclosure process at MIT, Grewal said. At proposal stage, individuals are asked three COI questions in every proposal that is submitted through MIT’s system:

  • Do they have a financial interest in the sponsor?
  • Will they be purchasing goods or services from the sponsor?
  • Could the results of the project have an impact on any entity in which they have a significant financial interest?

At the award stage, she said that a more extensive disclosure process is triggered, and that funds are not expended until disclosure requirements are met.

“However, it’s still largely an honor system. Institutions can only go by what individuals disclose to them. At the end of the day, institutions can have the clearest guidelines and financial thresholds and sophisticated disclosure systems, but decisions are still made by the individual on what is disclosed. At MIT, education on COI policy and process is a continually evolving and consistent effort, a strong partnership with faculty and research administrators. It’s important for faculty to know that they are not alone in this process, that there are resources available to help them make informed decisions about outside engagements.”

Fallout
When a researcher’s ethical lapses lead to resignation and abandoning administrative, research, and clinical responsibilities, there is often extensive fallout that extends beyond reputation and finances.

What happens with the researcher’s ongoing research and his or her laboratory personnel whose careers are dependent on the researcher? How do abandoned patients feel? How much retrospective review is needed for past research and publications? What becomes of the researcher’s legacy? And so on.

Over the years I’ve written a number of articles about the aftermath of fallen icons, including one related to AACR’s renaming one of its annual awards when it was revealed that the award’s namesake had made derogatory racial comments.

I pointed out then, and repeat now the importance of not always throwing the baby out with the bathwater, and providing sufficient context to distinguish the disgraced from that individual’s contributions.

Scientific Sacred Cows
I’ve also found that many individuals considered as “untouchable” or “sacred cows” are often treated as if they were beyond reproach and too important to be criticized, thereby receiving many passes on behavior that might not be tolerated in others.

And I’ve been warned away from pursuing certain stories because potential sources have either been too afraid to come forward on-the-record or claim that exposure—regardless of how truthful—of an individual or institution may do more harm than good.

It’s Not All About Sex
I contacted the National Institutes of Health regarding what policy was in place to continue research activities when a funded principal investigator was no longer able to continue functioning in that capacity.

NIH press officers responded via email with a the following statement:

“Typically, in an instance where the principal investigator or co-principal investigator named on the notice of award is placed on administrative leave because of the need to investigate an allegation of sexual harassment, the awardee organization would request a change of senior/key personnel supporting the NIH grant. When this occurs, NIH can take several actions, including approving a new lead principal investigator (PI) recommended by the grantee if scientifically appropriate, or suspending or terminating the grant. Generally, NIH views a replacement PI as the best course of action, when possible, to allow scientific progress of a peer-reviewed project and allow other personnel working on the grant, including in some cases the victim of harassment, to continue their research. Importantly, if NIH indirectly learns of an allegation of sexual harassment, we will contact the grantee institution to learn more, and among the range of possible actions, we may withdraw our approval of the PI if there is a reasonable basis to conclude the PI is no longer qualified or competent to perform the research objectives.”

When I replied that I was interested in a more extensive policy covering other areas of malfeasance, misconduct, or circumstances leading to inability to continue as a principal investigator, I received an email that said,” We appreciate your patience as we work on a response.”

However, despite stating my pending deadline, the response had still not been received by the time this story was posted. When it is made available, Onco’Zine will update the story.

This is the first in a periodic series exploring ethical issues in research.


This article was originally published as an editorial in Onco’Zine on October 9, 2018

Last Editorial Review: October 9, 2018.

Featured Image: Jose Baselga, MD, PhD, FASCO, presenting the results of a Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER, during the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2018. Courtesy: 2018 © ASCO/Brian Powers. Used with permission.

Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Eric Rosenthal Reports | A Personal Remembrance of Two Giants of Oncology: Jim and Jimmie Holland

James F. Holland, MD, one of the pioneers of combination chemotherapy and cancer cooperative group research, died at the age of 92 on March 22.  His wife, Jimmie C. Holland, MD, who was considered the founder of psycho-oncology, predeceased him by three months on Christmas Eve at age 89.

Jim was Distinguished Professor of Neoplastic Diseases at the Icahn School of Medicine at Mount Sinai in New York, and Jimmie was Wayne E. Chapman Chair in Psychiatric Oncology and attending psychiatrist at Memorial Sloan Kettering Cancer Center.

Photo 1.0: In the 1950s James (Jim) F. Holland and colleagues were considered the  “cowboys” of chemotherpy.

I knew both Jim and Jimmie, had interviewed them individually numerous times over many years, and considered them friends.  They both continued to work and contribute to their fields until the end, and always had new and interesting information to share.

I first met Jimmie in 1990 when I was chairing a meeting of a group I had founded, the NCI-Designated Cancer Centers Public Affairs Network, at MSKCC and our steering committee was treated to attending grand rounds with Jimmie Holland.  Several years later I was introduced to Jim.

At dinner a few years ago hosted by Stand Up To Cancer in honor of the PBS documentary series, “Ken Burns Presents Cancer: The Emperor of All Maladies,” Jimmie and I sat together and chatted most of the evening.  Later on, I thanked Jim for lending me Jimmie as my girlfriend. “As long as you’re not her boyfriend,” he responded with the wit and good humor that characterized him almost as much as his outspoken manner and colorful neckties.

When I began writing a series last year for MedPage Today about pioneers in oncology, my first call for an interview was to Jimmie, who had been encouraging me for many years to write a book about the cultural or social history of cancer.  She had promised to write the preface.

For the MedPage series I told her that I wanted to arrange separate interviews with her and then Jim over the next few weeks.

She replied that she thought it wise to start with Jim because of several health issues he’d been dealing with, and I took her advice.

A few months following publication of Jim’s profile, I called Jimmie again about scheduling a time to talk.   She did not respond immediately and finally replied that I should contact her again in several weeks.

When we spoke, she said that she had recently undergone surgery after developing a bilateral femoral arterial emboli, and how the experience—one of the few medical issues she had encountered during her long life–had enhanced her understanding of how so many of her cancer patients had felt.  She was, after all, the psychiatrist who had pioneered a field based on how people cope with a devastating disease rather than dealing with mental illness.

Our conversation, however, only lasted a short time since she was fatigued from her condition, so we rescheduled for November when she was up to speaking at length and about some things she had never discussed before.

That interview, which may have been her last, was published a month before she died in her Revolutionary-era home in Scarsdale, NY, surrounded by her family.

I wrote to Jim expressing my condolences but did not receive a reply.  Then in March during an interview with Larry Norton, MD, who considered Jim a mentor and was a longtime colleague of Jimmie’s at Memorial Sloan Kettering, we discussed how Jim was following the loss of Jimmie.  Larry said he had written to Jim several times but hadn’t heard back.  That conversation was days before learning about Jim’s death at home from respiratory failure.

During their early years in Buffalo, N.Y., during the 1950s, Jim was chief of medicine B at Roswell Park Cancer Institute, and Jimmie was head of psychiatry at Erie County Medical Center. During an 8-year period she also had five children taking 6-month leaves between births, while pursuing her professional career.

Jimmie would relate how she had spent many evenings listening to her husband and his colleagues discuss the early development of chemotherapy and how it was making a real difference in pediatric acute lymphoblastic leukemia.

Those colleagues included Emil “Tom” Frei III, MD, with whom Jim Holland co-founded the Cancer and Leukemia Group B (CALGB). The two went on to share the Lasker Award in 1972 with Emil J. Freireich, MD, and Donald Pinkel, MD.

 Jimmie said:  “It was an exciting time in chemotherapy with new drugs coming down the pike, and I’d asked them if they asked their patients how they felt about their cancer, which helped develop my interest in issues relating to the psychological care and support of patients facing catastrophic diseases.”

She added, however, that in those days medical oncologists were not paying much attention to their patients’ quality of life since they were too engaged in the big problem of finding cures.

“They thought my concerns were just temporary stopgaps,” she said. “But I was around when we saw the first Hodgkin’s survivors. In the 1960s, we suddenly began to see people surviving.”

She said that she persuaded her husband who was a co-founder and then-head of CALGB to start a psychiatry committee that enabled the fledgling field of psychosocial oncology to add quality-of-life questions into larger protocols, providing more of a scientific basis to what was perceived as a “soft” science.

In addition to cancer-related social events I usually spent time with the Hollands at the American Association for Cancer Research (AACR) and American Society of Clinical Oncology (ASCO) annual meetings.  Jim had served as president of both organizations, and every time I saw him, his inevitable reply to my, “How are you?” was always, “Still vertical, unlike many of my colleagues.”

I will sorely miss hearing that response at AACR later this month but know that Jim and Jimmie both led long, fruitful lives that had saved the lives and soothed the psyches and emotions of countless cancer patients and their loved ones.


This article part in a series of the revival of Eric Rosenthal Reports published in Onco’Zine and formerly featured in Oncology Times.


Last Editorial Review: April 3, 2018

First published in Onco’Zine on April 3, 2018

Featured Image: Laboratory glassware containing. Courtesy: © 2010 – 2018 Fotolia.  Used with permission. Photo 1.o: In the 1950s James (Jim) F. Holland and colleagues were considered the “cowboys” of chemotherpy. Courtesy: © 2010 – 2018 National Library of Medicine | National Institute of Health.  Used with permission.

Copyright © 2013 – 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Preclinical Data Supports the Development of XMT-1536 in a Broad Population of Patients with Ovarian Cancer

Update data from preclinical studies with XMT-1536, an antibody-drug conjugates or ADC being developed by Mersana Therapeutics targeting NaPi2b, were presented in a poster at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications, held  October 26 – 30, 2017 in the Pennsylvania Convention Center in Philadelphia, Pennsylvania.  was given by Rebecca Mosher, M.D., Executive Director, Translational Medicine, Mersana Therapeutics.[1]

The data confirms that XMT-1536 may offer positive results for patients with ovarian cancer, which ranks, according to the American Cancer Society, 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 75. Overall, a woman’s lifetime chance of dying from ovarian cancer is about 1 in 100.

The American Cancer Society estimates that in the United States in 2017 about 22,440 women will receive a new diagnosis of ovarian cancer. About 14,080 women will die from ovarian cancer.

This means that ovarian cancer represents a major unmet medical need.

Anti-sodium-dependent phosphate transport protein
XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein (NaPi2b; SLC34A2) immunoconjugate comprised of an average of 10-15 DolaLock payload molecules conjugated to XMT-1535, a proprietary humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform. NaPi2b is an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is scheduled to begin Phase I clinical trials in early 2018.


…the data … support … NaPi2b [as an] outstanding target for ADC development … and the Dolaflexin ADC platform allows us to fully exploit the advantages of this … target…


Outstanding target
“The data presented at AACR-NCI-EORTC further support that NaPi2b is an outstanding target for ADC development and that the Dolaflexin ADC platform allows us to fully exploit the advantages of this interesting target,” said Donald Bergstrom, M.D., Ph.D, Chief Medical Officer, Mersana Therapeutics.

“These results in ovarian cancer models are consistent with data we’ve previously presented on the broad activity of XMT-1536 in preclinical models of non-squamous non-small cell lung cancer (NSCLC). We look forward to initiating Phase I testing of XMT-1536 in patients with ovarian cancer, non-squamous NSCLC and other NaPi2b-expressing tumors by early 2018,” he added.

The study revealed that XMT-1536 induced at least a 50% median reduction in tumor volume relative to baseline in 10/19 (53%) primary patient-derived ovarian cancer xenograft models, that were selected for testing without prior knowledge of NaPi2b expression status. The activity of XMT-1536 was comparable in models derived from tumors from treatment-naïve patients as well as models that came from patients with heavily pre-treated tumors.

Target expression
When NaPi2b target expression was evaluated using a proprietary immunohistochemistry (IHC) assay discovered at Mersana in conjunction with XMT-1536, there was an association between NaPi2b IHC H-score and tumor volume change after XMT-1536 treatment. Among tumors with an H-score ≥70, 10/12 (83%) of models achieved 50% or greater reduction in tumor volume after XMT-1536 treatment, vs. 0/7 (0%) models with an H-score ‹70. Applying the same IHC assay to primary human ovarian tumors, 12/20 (60%) tested tumors had an H-score ≥70, indicating the majority of human ovarian tumors express levels of NaPi2b associated with deep regressions in response to XMT-1536 in pre-clinical models.

“We are extremely pleased with the results of this research and the progress the program has made to date,” said Rebecca Mosher, M.D., Executive Director, Translational Medicine, Mersana Therapeutics.

“The data described in the presentation suggest that XMT-1536 could be broadly active in ovarian cancer, and that we may have a diagnostic tool that could further enrich the patient population to enhance clinical benefit,” she further noted.


Last Editorial Review: October 30, 2017

Featured Image: Laboratory glass. Courtesy: © 2017. Fotolia. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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AACR 2017: Advancing Antibody-Drug Conjugate and Novel Immuno-Oncology

Multiple data presentations supporting Seattle Genetics’ advancing antibody-drug conjugate or ADC and immuno-oncology programs were presented at the Annual Meeting of the American Association for Cancer Research (AACR), being held April 1-5, 2017, in Washington, D.C.

Commenting on the number of these presentations, Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development, at Seattle Genetics, noted: “Our expertise in empowered-antibody innovation drives a substantial, advancing pipeline of more than a dozen clinical and preclinical programs, both ADCs and immuno-oncology agents.”

“Preclinical data presented at AACR support multiple ongoing clinical studies evaluating combination treatment of brentuximab vedotin and nivolumab (Opdivo®; Bristol-Myers Squibb Company) in relapsed Hodgkin and non-Hodgkin lymphoma and phase I trials of two proprietary immuno-oncology agents, SEA-CD40 and SGN-2FF, in solid tumors.

Drachman also said that “Seattle Genetics is transforming into a global, multi-product oncology company through dedication to scientific innovation and the needs of patients.”

Analysis
One of the presentations highlighted the clinical biomarker analyses of CD33 targeting vadastuximab talirine (SGN-CD33A; 33A), an ADC being broadly evaluated across multiple lines of therapy in patients with myeloid malignancies, including the ongoing global phase III CASCADE trial in newly diagnosed, older AML patients and phase I/II trial in patients with newly diagnosed myelodysplastic syndrome (MDS).

An analysis from a phase I monotherapy study in AML was presented in a poster presentation on Tuesday, April 4, 2017 (Abstract #CT120).

Immuno-Oncology
Researchers at Seattle Genetics are presenting preclinical data feature SEA-CD40 and SGN-2FF,  two immuno-oncology agents which are both in phase I clinical trials.

SEA-CD40, an innovative immuno-oncology agent, is one of Seattle Genetics non-ADC programs and uses a novel sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody targeting CD40.  The approach is designed to empowering antibodies and is considered complementary to the company’s ADC technology. It builds on our extensive experience targeting CD40, an immune-activating receptor capable of driving an anti-tumor response.  Data from pre-clinical studies, presented in a poster on Tuesday, April 4, 2017 (Abstract #3647), suggests that the investigational compound SEA-CD40 may be o able to stimulate a patient’s own immune system to fight their cancer.

In the poster presentation, the researchers showed that treatment of CD-40 transgenic mice with SEA-CD40 resulted in cytokine induction and B-cell depletion.

The pre-clinical data focuses on the mechanism of action through activation of anti-tumor immune response and potential for combination with checkpoint inhibitors. SEA-CD40 targets the protein CD40 using Seattle Genetics’ proprietary sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody.[1]

SEA-CD40 is currently under investigation in a phase I trial in metastatic or unresectable solid tumors and hematologic malignancies.

SEA-2FF
This year Seattle Genetics also presented pre-clinical data on a novel small molecule, 2-fluorofucose (SEA-2FF).  This investigational compound blocks cellular incorporation of a sugar (fucose) whish is shown to have anti-tumor activity by two distinct mechanisms. The inhibition of fucosylation of proteins is intended to stimulate the immune system and slow the growth and spread of cancer cells.

Pre-clincal data demonstrates that SEA-2FF, as a single oral agent, delays the growth of solid tumors in multiple xenograft models.  But SEA-2FF also enhances the antibody-mediated immune response to cancers using a tumor vaccine model.

Furthermore, ongoing phase I study of SGN-2FF in patients with relapsed or refractory (advanced) solid tumors, including non-small cell lung cancer, were highlighted in an oral presentation during the New Drugs on the Horizon symposium on Sunday, April 2, 2017 (Session #DDT02-02).

Combination treatment
During this year’s annual meeting, Seattle Genetics and Unum Therapeutics presented pre-clinical data evaluating combination treatment with Antibody-Coupled T cell Receptor (ACTR) engineered autologous T cells and an antibody targeting B-cell maturation antigen or BCMA.

The ACTR technology enables the programming of a patient’s immune system to attack tumor cells when co-administered with tumor-specific therapeutic antibodies.  The pre-clinical data support clinical evaluation of a humanized non-fucosylated anti-BCMA antibody, known as SEA-BCMA, being developed using Seattle Genetics’ novel sugar-engineered antibody (SEA) technology, and ACTR T cell combination treatment in multiple myeloma patients.

Designed to engage the Fc domain of therapeutic antibodies, the ACTR technology, is a universal, engineered T cell therapy consisting of the extracellular domain of human CD16 and the intracellular T cell co-stimulatory and signal domain.

One presentation highlighted data from pre-clincal studies on targeting BCMA-positive multiple myeloma cells with ACTR in combination with SEA-BCMA.[2] In this poster (abstract #4605), Tooba Cheema, Ph.D, a senior scientist at Unum Therapeutics, explained that the cell surface protein BCMA, which recently has emerged as an attractive  therapeutic target in multiple myeloma, is expressed on cells of several cancer types, including multiple myeloma and other B cell malignancies. Cheema confirmed that BCMA expression is restricted expression on plasma cells with little to no expression on other, normal, cell, but is upregulated on the surface of specific cancer cells.

A number of different approches designed to target BCMA are currently under way, including chimeric antigent receptor (CAR) T-cell therapies, bispecific antibodies and ADCs.

One of these approaches involves a humanized afucosylated anti-BCMA antibody, SEA-BCMA, which binds to antibody-coupled T cell receptor (ACTR) expressing T cells with high affinity and mediates T cell activation, potent cytotoxicity, cytokine release and proliferation across a wide range of BCMA-expressing multiple myeloma cells.

In preclinical studies, the researchers noted ACTR activity specific to SEA-BCMA.  They also noted no activity on BCMA negative tumor lines. Based on these studies, they believe SEA-BCMA may offer a valid option for the treatment of patients with multiple myeloma.

Immunogenic cell death
A presentation describing the ability of brentuximab vedotin (Adcetris®) to activate antitumor immune responses, supports continued clinical evaluation of the agent in combination with checkpoint inhibitors.

An evaluation of the preclinical data confirmed the ability of brentuximab vedotin to induce immunogenic cell death was be presented in a poster presentation on Wednesday, April 5, 2017 (Abstract #5588). These data demonstrate that brentuximab vedotin-treated tumor cells initiate an anti-tumor immune response alone and, to a greater extent, in combination with anti-PD-1 agents, and support combination strategies with immuno-oncology regimens, such as the ongoing phase I/II/ clinical trials evaluating brentuximab vedotin and nivolumab in relapsed Hodgkin and non-Hodgkin lymphoma.


Last Editorial Review: April 5, 2017

Featured Image: United States Capitol Building, Washington, DC, capital of the United States of America Courtesy: © 2017 Fotolia. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Preclinical Data on XMT-1522 Supports Efficacy and Tolerability

During the 108th Annual Meeting of the American Association for Cancer Research (AACR), held April 1 to 5, 2017, in Washington, D.C, Mersana Therapeutics, a clinical-stage biotechnology company focused on discovering and developing a pipeline of antibody drug conjugates (ADCs) based on its proprietary Fleximer® technology, presented data that highlighted the company’s emerging antibody drug
conjugate (ADC) XMT-1522.

XMT-1522 consists of a novel human IgG1 anti-HER2 monoclonal antibody and a novel, auristatin-based cytotoxic payload (Auristatin F-hydroxy-propylamide, AF-HPA). An average DAR of 12 AF-HPA molecules is achieved via a biodegradable polymer conjugation platform.

XMT-1267
In two poster presentations scientists from Mersana confirmed that the small molecule Auristatin F – HPA (XMT-1267), which has the capacity for bystander effect, is a primary ADC drug release product.

They found that XMT-1267 is further metabolized in the tumor to form Auristatin F (XMT-1521), the most abundant XMT-1267 metabolite.

XMT-1521, which is negatively charged and not freely cell permeable, is observed in the tumor at significant levels two weeks post-administration of XMT-1522, supporting a trapping effect of this active metabolite.

XMT-1522
XMT-1522 is Mersana’s lead ADC compound, and is being developed for the treatment of patients with HER2-positive cancers, as well as for patients with HER2-expressing tumors not meeting the current diagnostic definition of HER2-positive.

The second poster presentation, presented in a session on Monday, April 3, demonstrated in pre-clinical models that XMT-1522 and its active release product, XMT-1267, can lead to immunogenic cell death. The potential for XMT-1522 to have monotherapy activity in HER2-expressing NSCLC, as well as a rationale for combinations of XMT-1522 and immunomodulatory therapies in NSCLC, was also reported.[2]

Overall, the data presented at AACR included results from the combination of XMT-1522 + the checkpoint inhibitor pembrolizumab tested in a patient-derived HER2-expressing PDX models in a mouse with a humanized immune system. In these trial expression of huPD-L1 in the tumor was confırmed by FACS and immunohistochemistry (IHC). Lymphocyte sub-populations were quantifıed in whole blood and in tumor by FACS and IHC. XMT-1522 treatment alone induced tumor growth delay after 3 weekly doses of 1 mg/kg. Pembrolizumab as a single agent administered every 5 days for 6 doses (q5dx6) at a dose of 2.5 mg/kg led to less tumor growth delay than XMT-1522 treatment. The combination of these two treatment regimens resulted in a better response than either of the two monotherapies. These data provide a rationale for XMT-1522 to be tested clinically as a single agent in HER2-expressing NSCLC, as well as a rationale for combination of XMT-1522 and immunomodulatory therapies in NSCLC.[2]

“The pre-clinical support for the potential benefit to patients of XMT-1522 continues to strengthen and we are excited to have initiated clinical development for the program,” noted Anna Protopapas, President and Chief Executive Officer of Mersana.

Progress
“The presentations at AACR highlighted the progress we have made with our lead antibody drug conjugate, XMT-1522, as an ADC-based therapy, but also in the important field of immuno-oncology, where the data suggests the compound’s potential as a monotherapy in HER2-expressing non-small-cell lung cancer (NSCLC), as well as in combination with immunomodulatory therapies in NSCLC,” Protopapas added

“Our presentation in immuno-oncology strongly suggests that XMT-1522 and its active release molecule, XMT-1267, lead to immunogenic cell death, and can significantly enhance the effect of immuno-oncology agents such as checkpoint inhibitors,“ said Timothy B. Lowinger, Ph.D., Chief Scientific Officer of Mersana
Therapeutics.

“The second presentation demonstrates Mersana’s deeper understanding of XMT-1522’s drug metabolism and pharmacokinetic (DMPK) properties, which support the potential of Mersana’s Dolaflexin ADC platform to provide a greater therapeutic index by simultaneously improving efficacy, via greater payload
delivery, and tolerability due to the unique pharmacology designed into our novel auristatin payload.”


Last Editorial Review: April 2, 2017

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AACR 2017: Nine Presentations Feature ImmunoGen’s Approch to ADC development

Earlier today, ImmunoGen, a company at the forefront of antibody-drug conjugates (ADC-) development for the treatment of cancer, announced that nine abstracts highlighting the breath of the Company’s expertise in ADCs, will be presented at the upcoming annual meeting of the American Association of Cancer Research (AACR) to be held from April 1-5, 2017 in Washington D.C.

AACR Logo_NewsroomOver the last decades, ImmunoGen has built a large portfolio of ADC technologies, including alternative types of cancer-killing agents such as the company’s tubulin-acting maytansinoids and their DNA-acting IGNs as well as a variety of linker chemistries. This year, the presentations at AACR will cover a wide-array these innovations, including further advancements to linkers and payloads and novel targets for both solid tumors and hematological malignancies.


“…the data being presented at AACR further validates our full-spectrum of knowledge and leadership in this space…”


“ImmunoGen has an unmatched expertise and understanding of the core components of ADCs and the data being presented at AACR further validate our full-spectrum of knowledge and leadership in this space,” said Richard Gregory, Ph.D., ImmunoGen’s chief scientific officer. “ImmunoGen will be presenting nine abstracts at the conference with preclinical data demonstrating technology advances that will enable us to continue to drive innovation in ADC approaches.”

Technology
ImmunoGen’s lead product candidate, mirvetuximab soravtansine, is in a Phase III trial for FRα-positive platinum-resistant ovarian cancer, and is in Phase Ib/II testing in combination regimens for earlier-stage disease.  The company’s technology is further used in ado-trastuzumab emtansine (Kadcyla®), an antibody-drug conjugate marketed and distributed by Genentech/Roche, in three other clinical-stage product candidates being developped by ImmunoGen, and in new drug development programs conducted in partnership with Amgen, Bayer, Biotest, CytomX, Lilly, Novartis, Sanofi and Takeda.

AACR 2017
Each year, the annual meeting of the American Association of Cancer Research highlights the best cancer science and medicine from institutions all over the world. Attendees are invited learn more detailed news about how to apply exciting new concepts, tools, and techniques in the development of novel anticancer drugs and introduce new ways in their own research.


Abstract Title Authors Date &Location Description
Platform linker and payload innovations
# 75 Comparison of site-specific and lysine-linked indolino-benzodiazepine antibody-drug conjugates (ADCs). Bai C, Nicholas C. Yoder NC,  Wilhelm A,  Adams S, Whiteman K, Lee J, O’Callaghan K, Maloney E, et al. April 2, 2017, 1:00-5:00 PM | Section 3 While site-specific conjugation can lead to improved efficacy and tolerability, the advantages and disadvantages of site-specific conjugation should be carefully considered for every ADC candidate.
# 71 Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker. Qiu Q, Wu R, Lanieri L, Maloney E, Skaletskaya A, Jin S, Wang L, Ab  O, et al April 2, 2017, 1:00-5:00 PM | Section 3 Folate receptor (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. M9346A-NL-DM is a novel ADC, employing a new linker, with enhanced bystander activity and anti-tumor activity that can target tumors with heterogeneous expression of FRα.
 # 2186 Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo. Widdison WC, Costoplus JA, Ponte JF, Lanieri L, Setiady Y, Dong L, Skaletskaya A, Wu R, Qiu Q,  et al. April 3, 2017, 1:00 – 5:00 PM | Section 8 A new promising type of maytansinoid ADC provides a high degree of bystander killing, improved activity in tumor models in vivo, and has a differentiated mechanism of metabolite release.
# 53 Antibody-drug conjugates (ADCs) of peptide-linked Indolino-Benzodiazepine (IGN) DNA-alkylator provides improved anti-tumor activity over that of a crosslinker. Miller ML, Shizuka M, Ponte JF, Lanieri L, Vitharana D, Qiu Q, Reid EE, Archer KE, et al. April 2, 2017, 1:00-5:00 PM | Section 3 Preclinical research shows that DNA-alkylating IGNs provide improved anti-tumor activity over that of a DNA-crosslinking ADC.
Preclinical research focused on novel targets
#37 Novel antibody-drug conjugates targeting ADAM9-expressing solid tumors demonstrate potent preclinical activity. Hicks SW,  Yoder NC, Loo D, Muvaffak A,  Zhou Y, Fuller ME,  McShea MA,  Themeles  M, et al. April 2, 2017, 1:00-5:00 PM | Section 2 ADAM9 is a promising cell surface target for antibody-drug conjugate development that is overexpressed in multiple solid tumor indications relative to corresponding normal tissues.
#38 Target validation, antibody discovery and preclinical data supporting ADAM9 as an antibody-drug conjugate therapeutic target for solid tumors. Scribner JA, Barat B, Hicks SW,  Yoder NC, Son T, Widjaja L, Diedrich G, Gorlatov  S, et al April 2, 2017, 1:00-5:00 PM | Section 2 These data demonstrate that anti-ADAM9 ADCs exhibit antitumor activity against a broad panel of ADAM9-positive malignancies and cause durable remissions in preclinical models at doses expected to be clinically achievable. Anti-ADAM9 ADCs represent a promising therapeutic strategy to a wide range of ADAM9-expressing tumors.
#45 In vitro and in vivo activity of a novel c-Met-targeting antibody-drug conjugate using a DNA-alkylating, indolinobenzodiazepine payload. Lai KC, Muvaffak A, Li M, Themeles M, Sikka S, Donahue K, Hicks SW, Romanelli A, Chittenden T April 2, 2017, 1:00-5:00 PM | Section 2 cMet dysregulation and/or overexpression are associated with tumor progression, metastasis and poor prognosis in numerous cancers. An anti-cMet antibody conjugated with the payload DGN549 exhibits compelling, c-Met targeted anti-cancer activity in vitro and in vivo, and represents a promising therapeutic strategy to deliver a potent cytotoxic agent to tumor cells bearing a wide range of c-Met expression.
Preclinical research focused on B-cell targets
#2651 A novel CD19-targeting antibody-drug conjugate, huB4-DGN462, shows promising in vitro and in vivo activity in CD19-positive lymphoma models. Gaudio E, Tarantell C, Arribas AJ, Bordone RP,  Rinaldi A, Stussi G,  Zucca E, Rossi D, et al. April 3, 2017, 1:00 – 5:00 PM | Section 26 CD19 is a cell surface membrane protein expressed in most mature and immature B cell neoplasms, which make it a promising target for ADC therapy for B cell malignancies. A novel CD19-targeting ADC presents strong preclinical anti-lymphoma activity.
#1073 Increased internalization and processing of the CD37-targeting antibody-drug conjugate, naratuximab emtansine (IMGN529), in the presence of rituximab leads to enhanced potency in diffuse large B-cell lymphoma models Hicks SW, Lai KC, Yi Y, Shah P, Gavrilescu CL, Ponte J, Sloss CM, Romanelli A. April 3, 2017, 8:00-12:00 PM | Section 1 Data show enhanced activity of rituximab plus IMGN529 combination in DLBCL models, supporting the clinical development of this combination.

Last Editorial Review: March 1, 2017

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Phase I Trial of SGN-CD352A in Relapsed or Refractory Multiple Myeloma Initiated

This week the first patient enrolled in a multi-center phase I clinical trial of SGN-CD352A for the treatment of patients with relapsed or refractory (r/r) multiple myeloma. SGN-CD352A is an investigational CD352-targeted antibody-drug conjugate (ADC) utilizing Seattle Genetics’ proprietary ADC technology, an engineered cysteine antibody (EC-mAb) stably linked to a highly potent cytotoxic agent called a pyrrolobenzodiazepine (PBD) dimer. [1]

Antibody-drug conjugates are designed to selectively deliver cell-killing agents to tumor cells, and thus may reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

CD352 is broadly expressed on B-cell cancers including multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, while exhibiting low expression on normal white blood cells. The CD352 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD352-expressing cells.

Multiple Myeloma
Multiple myeloma is a rare and aggressive cancer that forms in white blood cells called plasma cells. Normal, healthy, plasma cells are found in the bone marrow are an important part of the immune system. In contrast, malignant or cancerous plasma cells, which can crowd out healthy blood cells, impair bone strength and weaken the immune system.[2]

The immune system is made up of several types of cells that work together to fight infections and other diseases. Lymphocytes are the main cell type of the immune system – major types of lymphocytes are both T cells and B cells.

Despite recent medical advances, the disease remains an incurable disease in which patients eventually progress and die. Within one year of first-line therapy, 32% of transplant patients and 44% of non-transplant patients relapse. Remission periods are typically shorter for each subsequent line of therapy, with some patients receiving more than four lines of treatment over the course of their disease. After lymphoma and leukemia, multiple myeloma is the third most common blood cancer in the US. According to the World Health Organization, in 2015 more than 124,000 new cases of multiple myeloma were diagnosed worldwide and more than 87,000 people died from the disease. [3]

Trial design
The new clinical trial (NCT02954796) is designed to assess the safety and antitumor activity of SGN-CD352A. This study represents Seattle Genetics’ first clinical-stage ADC program in development for multiple myeloma, demonstrating the breadth of potential therapeutic applications for its industry-leading ADC technology platform.

“More than 124,000 people worldwide are diagnosed annually with multiple myeloma, most relapsing or becoming resistant to current therapies,” noted Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.

“SGN-CD352A is a novel targeted investigational compound for multiple myeloma, and it is our latest antibody-drug conjugate, or ADC, in an expanding and robust pipeline of clinical stage empowered antibody therapies to address blood cancers and solid tumors. As we begin clinical development of our first compound for multiple myeloma, we continue to explore the broad potential of our ADC technology platform for people with cancer,” Lechleider concluded.


“More than 124,000 people worldwide are diagnosed annually with multiple myeloma, most relapsing or becoming resistant to current therapies”


The phase I, open-label multicenter clinical study is designed to evaluate the safety and preliminary antitumor activity of SGN-CD352A as a single agent in adults with relapsed or refractory multiple myeloma. The trial will be conducted in two parts, with a dose escalation part to identify the maximum tolerated dose of SGN-CD352A followed by an expansion part to further define safety and antitumor activity. SGN-CD352A will be administered every four weeks, and the study will enroll approximately 75 relapsed or refractory patients at multiple centers in the United States.

AACR 2016
Preclinical SGN-CD352A data presented at the 2016 American Association of Cancer Research (AACR) Annual Meeting demonstrated that SGN-CD352A specifically binds to target cells and induces potent antitumor activity in both multiple myeloma and non-Hodgkin lymphoma disease models. In addition to being a potential new monotherapy for multiple myeloma, the tolerability profile from preclinical results suggests that SGN-CD352A may be combined with current standard of care treatments for multiple myeloma.


Last Editorial Review: January 5, 2017

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Best ADC Platform Technology Awarded to Mersana Therapeutics

This week, during the 7th World ADC Conference in San Diengo, Mersana Therapeutics, a biotechnology company focused on discovering and developing a pipeline of antibody-drug conjugates or ADCs based on its proprietary Dolaflexin® technology, received “Best ADC Platform Technology” award for its Dolaflexin platform.

Now in their third year, the World ADC Awards are designed to showcase excellence within antibody drug conjugate research. The awards reward the innovation, leadership, and devotion shown by the best companies, teams, and individuals in the industry. Across eight categories the the organizers of the event recognize the extraordinary endeavours, teamwork and commercial acumen that has propelled the field to the forefront of cancer research today.

Mersana was also selected as a runner-up in the “New Drug Developer” category.


“Receiving this award underscores the scientific innovation of Mersana’s Discovery team and potential of …[the] Dolaflexin platform…”


The 7th World ADC’s “Best ADC Platform Technology” award acknowledges the best linker or payload platform technology and is selected for the system’s novelty and originality as well as scientific and commercial validation of the platform.  In addition, the “New Drug Developer” class, recognizes an emerging company involved in the (early) development of antibody-drug conjugates that it has made significant progress within its preclinical pipeline with at least one pipeline drug.

Dolaflexin Platform
Dolaflexin, Mersana’s lead platform technology, is based on the company’s Fleximer polymer backbone and a proprietary aurastatin payload. Fleximer allows for significantly higher DAR (Drug to Antibody Ratio) or payload per antibody (>15) than other ADC approaches resulting in higher efficacy. Furthermore, Fleximer-based immunoconjugate molecules have been shown to have superior efficacy, including with targets previously considered not amenable to antibody-drug conjugate approaches.

The proprietary auristatin payload is designed to be highly potent when released in the tumor cell but to subsequently be metabolized into less potent agent hence resulting in improved tolerability. In early and pre-clinical studies Dolaflexin based ADCs have been shown to be highly efficacious while maintaining a wider therapeutic index than traditional ADCs approaches.

“Receiving this award underscores the scientific innovation of Mersana’s Discovery team and potential of our Dolaflexin platform,” noted Anna Protopapas, President and Chief Executive Officer of Mersana.

“We are grateful to the Conference for this recognition and will continue to commit ourselves to developing novel cancer treatments to address ongoing patient needs,” she added.

Pipeline
Using the company’s Dolaflexin technology platform, Mersana has rapidly developed a burgeoning oncology pipeline that includes two compounds that are advancing towards clinical studies. XMT-1522, Mersana’s first pipeline product, defines a new class of HER2-targeted therapies.

The investigational drug is an anti-HER2 ADC that incorporates HT-19, a novel, human anti-HER2 antibody optimized for cytotoxic payload delivery.[1]  In addition HT-19 was selected to be non-competitive for HER2 binding with existing therapies – trastuzumab or pertuzumab, to allow the potential of combination therapies.

XMT-1522 is armed with about 15 auristatin molecules per antibody, making it highly potent in tumor models that express relatively low amounts of the HER2 protein. XMT-1522 has the potential to extend HER2-targeted therapy beyond the current HER2+ population into patients with lower levels of HER2 expression.

The second pipeline product, XMT-1536, is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody. Earlier this year during the 2016 annual meeting of the American Association for Cancer Research (AACR), data were presented that demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models.[2]

investigational compound known as XMT-1536 may help patients with NaPi2b-expressing tumors. Preclinical data with this immunoconjugate product demonstrated significant anticancer activity in NSCLC and ovarian cancer tumor models. Based on the data presented during the annual meeting of the AACR , Mersana advanced XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors.


Last Editorial Review: October 13, 2016

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Clinical Updates Confirming Advances and Meaningful Benefits for Patients

Earlier this year, during the meetings of the American Association for Cancer Research (AACR), held April 16-20 in New Orleans, LA, and the Protein and Antibody Engineering Summit (PEGS) in Boston, MA (April 25 – 29), multiple presentations showed how antibody-drug conjugates (ADCs) have, over the last decade, really revolutionized the field of cancer chemotherapy.

With good reason, ADCs have, essentially, become all the rage for pharmaceutical oncology drug development pipelines.

While the success of the currently approved and marketed ADCs, brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche/Immunogen), has, as one expert explained, been tough to follow, it’s exciting to see that the hard work by dedicated scientists and clinical investigators is indeed bearing fruit!

With >50 ADCs in clinical trials, and an average clinical development time of ~6 – 12 years, the expectation is that in the next 3 – 4 years the number of new, approved, ADCs will increase dramatically.

It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges … in the development of novel antibody-drug conjugates…

Hurdles
The complexity of ADCs present unique development challenges. But what are some of the hurdles to be expected in bringing novel ADCs to the clinic? Following the first generation of ADC chemistries, what are some of the preclinical and clinical lessons and how have these experiences been applied?

New ADCs in clinical development are directed against a range of different targets. However, there are only a limited number of cytotoxic drugs, including calicheamicin, auristatins, maytansinoids, duocarmycins and pyrrolobenzodiazepines (PBDs) confirming the difficulties of finding fitting cytotoxic drugs as payloads in ADCs. How do these highly potent agents support an average of drug-to-antibody ratio (DAR) of 2 to 4? Are they not too hydrophobic? Are they linkable? Are they accessible by simple synthetic pathways? Manufacturable? Is there a relationship between targeted receptor number and the potency of the targeted cytotoxic drug required for therapeutic efficacy?

How can we design a linker in a ligand-targeted drug conjugate that is stable in circulation and cleavable upon endocytosis into tumor cells? What about a case for moderate toxic payloads? What about the sensitivity of cytotoxic agents to multidrug resistance (MDR) mechanisms?

Meeting the challenge
It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA) of existing and new ADCs, how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel, targeted, drugs may have the highest clinical benefit. [1]

During the 2016 AACR meeting in April, results from the I-SPY2 TRIAL, in which investigators tested if ado-trastuzumab emtansine + pertuzumab could bring a substantially greater proportion of patients to the primary endpoint of pathological complete response (pCR) compared with paclitaxel + trastuzumab, showed that the combination of ado-trastuzumab emtansine + pertuzumab substantially improved pCR for all subgroups of HER2-positive breast cancers compared with those in the control group. [2]

Investigators expect that this combination will most likely succeed in a confirmatory 300-patient, neoadjuvant, phase III, randomized trial testing ado-trastuzumab emtansine + pertuzumab against paclitaxel + trastuzumab. [2]

PEGS Summit
In late April, during the PEGS Summit in Boston, attendees discussed the complexity of antibody-drug conjugates with its many moving parts. The confirmed consensus is that these ‘moving parts’ make the field of antibody-drug conjugates incredibly challenging, and yet, it offers scientists a full spectrum and potential for innovation. From new targeting ligands to new conjugation methods, from multiple payloads to changing the drug-antibody ratio (DAR), all these are challenging the convention for the design and development of next-generation ADCs.

Progress in site-specific conjugation modalities, optimization of linkers with balanced stability and identification of novel, potent cytotoxic agents are expected to pave the way for a better understanding of factors such as ADC efficacy, PK and safety. A robust clinical pipeline, evolving clinical data, technological advancements and a better understanding of the biology of cancer and hematological malignancies, is expected to aid the development of these novel ADCs.

ASCO 2016
This year, the theme of the annual meeting of the American Society of Clinical Oncology (ASCO) to be held June 3 – 7 in Chicago, Ill. is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. [3]
The 2016 theme is expected to reinforces the inextricable link – a necessity – between ongoing clinical research and advances in patient-centered care. This theme is expected to be evident when the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry – crucial in the development of novel ADCs – will be presented.

As the executive editor of ADC Review / Journal of Antibody-drug Conjugates (published by InPress Media Group), I’m looking forward to see the updated results from a large number of (ongoing) clinical trials during ASCO this year. In addition to updates for brentuximab vedotin and ado-trastuzumab emtansine, oral and poster presentations during ASCO will include the latest – often late breaking abstracts – for [3]:

  • Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (IMMU-132), being developed by Immunomedics;
  • Rovalpituzumab tesirine (Rova-T/SC16LD6.5; Stemcentrx/AbbVie), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate for the treatment of recurrent or refractory small cell lung cancer (SCLC);
  • An anti-PSMA ADC (Ambrx) being developed for the treatment of patients with prostate cancer and glioblastoma multiforme;
  • Enfortumab vedotin (Agensys), a human anti-nectin-4 antibody conjugated to monomethyl auristatin E (MMAE) for the treatment of multiple solid tumors;
  • Inotuzumab ozogamicin (Pfizer) for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia;
  • Anetumab ravtansine (BAY 94-9343) an anti-mesothelin antibody drug conjugate for the potential treatment of mesotheliomas as well as ovarian and pancreatic cancers;
  • ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors;
  • Mirvetuximab soravtansine (IMGN853; Immunogen), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer;
  • Lifastuzumab vedotin, also known as DNIB0600A and RG-7599 is being developed by Genentech/Roche. In clinical trials lifastuzumab vedotin is compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.

In addition to these ADCs, results are expected for SAR566658, ABT-414 and other ADCs.

This year, the annual meeting of the American Society of Clinical Oncology is expected to draw approximately 30,000+ scientists, clinicians, (patient) advocates, and others who will listen, learn and discuss advances in the treatment of cancer.

Our editorial team will be present in Chicago to bring you exciting news and (late) breaking (clinical) updates as well as interviews with the dedicated scientists, physicians and other professionals involved in ongoing research.

Expect to see reports and stirring news from ongoing clinical trials with novel antibody-drug conjugates, confirming the exciting advances and meaningful benefits for patients – now and in the future.


Click here to see an overview of oral and poster presentations of antibody-drug conjugates to be presented at ASCO this year. For additional information to plan your meeting attendance, visit ASCO’s iPlanner page.

Last Editorial Review: May 10, 2016

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CytomX and AbbVie Jointly Develop and Commercialize Probody-drug Conjugates Directed Against CD71

Antibody-drug conjugates or ADCs combine the cytotoxic potential of chemotherapeutic drugs with the specificity of monoclonal antibodies.  One of the critical parameters effecting the efficacy, therapeutic window, and toxicity profile of ADCs is the selection of the an appropriate target.

Novel targets of antibody-drug conjugates have typically been selected by identifying transmembrane antigens that are highly expressed in tumors but are low or absent in normal, healthy, tissues.

However, the number of potential targets meeting these requirements is limited.  Scientists have long hypotesised that this may be caused because the expression of these targets in a specific tumor is not high enough for optimal efficacy, or, in contrast, the expression of the target in normal, healthy, tissues is too high, leading to unexeptable toxicity.

One alternative, Probody™ Drug Conjugates (PDCs),  being developed by CytomX Therapeutics, an oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics, are designed to take advantage of the unique conditions of a tumor’s microenvironment.

PDCs remain inactive until proteolytically activated in the tumor microenvironment and may have the potential to enable targeting of more desirable tumor antigens with higher, more persistent and more homogeneous expression in tumors, while limiting toxicity due to interaction with these antigens in normal tissues. In essence, Probody-drug conjugates mask use a masking peptide designed to limit binding to healthy tissue, thereby minimizing toxicities.

While the tumor-targeting features of an antibody are thus enhanced, the drug activity in healthy tissue is reduced.  As a result, probody therapeutics bind selectively to tumors and avoid binding to healthy tissue, to minimize toxicity and potentially create safer, more effective therapies.

Desirable target
Transferrin receptor 1 (TfR1), also known as CD71, which is ubiquitously expressed on the surface of dividing, normal or healthy cells as well as a number of solid and hematologic malignant cancer cells, mediates the uptake of transferrin-iron complexes (required for cell division and cannot be down regulated by tumors) is an example of a highly desirable antibody-drug conjugate target. [1]

One of the reasons is the well-characterized ability of CD71 to efficiently internalize and deliver a payload intracellularly. Another reason is that CD71 is expressed homogeneously in high levels (3+ expression by IHC) in almost all tumor types, including in metastatic disease.

But because CD71 is also expressed on multiple normal, healthy, cell types, including many progenitor hematological cells, scientists have had doubts about the possibility to develop a CD71-targeted antibody-drug conjugate since this expression in normal dividing cells prohibits development of a traditional antibody-drug conjugate.

To enable targeting of CD71, scientists at CytomX therapeutics developed an anti-CD71 Probody-drug Conjugate or PDC, which can be activated by multiple proteases in the tumor microenvironment. However, while activated in the tumor microenvironment, the anti-CD71 probody-drug conjugate remains in a relatively inactive form while in circulation and in normal tissues.

In mouse models of lymphoma, breast cancer and lung cancer the novel anti-CD71 prosody-drug conjugate produces complete tumor regressions at therapeutic doses.

Consistent with their hypothesis that it would be difficult to develop an anti-CD71 antibody-drug conjugate, treatment of cynomolgus monkeys with an anti-CD71 antibody-drug conjugate at doses that were efficacious in mouse tumor models caused life-threatening depletion of CD71-expressing hematopoietic cells, including neutrophils, lymphocytes and red blood cells (RBCs).

In contrast, these toxicities were not observed in monkeys treated with the same dose of the anti-CD71 probody-drug conjugate, consistent with the Probody therapeutic avoiding interaction with these normal cells.

During the 2016 annual meeting of the American Association for Cancer Research (AACR), being held April 16 – 20 in New Orleans, researchers presented data from preclinical studies showing that probody drug conjugates can safely and effectively target attractive tumor antigens like CD71 which have been difficult to address with traditional antibody-drug conjugates (Poster #2975).

The presented data also supported the development potential of Probody therapeutics directed against CD71 in multiple different cancers, demonstrating that these novel drugs can safely and effectively target tumor antigens.

Collaboration
Following the AACR meeting, CytomX Therapeutics and Abbie, a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories, announced that they have entered have entered into a collaboration to co-develop and co-commercialize probody-drug conjugates against CD71.

“We believe that the Probody platform provides a differentiated opportunity to combine with our strength in antibody drug conjugates,” noted Steve Davidsen, Ph.D., vice president, oncology drug discovery at AbbVie.

“We are encouraged by the promising preclinical data that CytomX has generated for their probody-drug conjugate programs to-date and look forward to working closely with their team. This collaboration will enable us to expand our innovative pipeline in antibody drug conjugates and leverage our strength in that area to previously unexplored targets,” Davidsen explained.

“This collaboration is another important step toward achieving CytomX’s vision of transforming lives with safer, more effective therapies and allows us to further advance our broad pipeline of Probody therapeutics,” said Sean McCarthy, D.Phil., president and chief executive officer at CytomX.

“AbbVie has demonstrated leadership in developing antibody drug conjugates and we look forward to collaborating with their team to realize the full potential of our CD71 Probody drug conjugate program and additional oncology targets,” he continued.

Agreement
Under the terms of the agreement, CytomX and AbbVie will co-develop a probody-drug conjugate against CD71, with CytomX leading pre-clinical and early clinical development. AbbVie will lead later development and commercialization, with global late-stage development costs shared between the two companies.

CytomX will receive an upfront payment of $30 million and is eligible to receive up to $470 million in development, regulatory and commercial milestones, pending the achievement of pre-determined outcomes. AbbVie will lead global commercial activities with CytomX eligible to receive a profit share in the U.S. and tiered double-digit royalties on net product sales outside of the U.S. CytomX retains an option to co-promote in the U.S.

AbbVie also receives exclusive worldwide rights to develop and commercialize probody-drug conjugates against up to two additional, undisclosed targets.  According to a statement of the companies, should AbbVie pursue these targets, CytomX is eligible to receive additional milestone and royalty payments per target on any resulting products.

CytomX’s lead probody-drug conjugates, CX-2009, directed at CD166, is currently in the IND-enabling stage. Other probody-drug conjugates programs are being assessed for advancement into clinical investigation.

In addition to the established partnership with AbbVie, CytomX has also established partnerships with Pfizer and ImmunoGen for multiple therapeutic targets and programs.


Last Editorial Review: April 21, 2016

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