Hands-on Workshops!

1. 5th Antibody Generation, Engineering & Design Conference
• Frankfurt, Germany
• Le Meridien Parkhotel, Frankfurt, Germany
• 29th of February 2012
• Half-Day Workshop February 29th: Latest Advances in Reducing the Risk of Immunogenicity: Deimmunization and Tolerance Induction
• Email Curtis for the discount code by clicking here
2. Westin Immunogenicity Seminar: Faster & Safer Protein Medicine & Vaccine Design
• Tokyo, Japan: 16 and 19th March 2012
• The Westin Hotel, Tokyo, Japan
• Seminar – March 16th; Hands-on Training – March 19th.
• Email Frances Terry to sign up by clicking here.
3. Providence – iVAX (web-based tool for vaccine design). 
• The Institute of Immunology and Informatics will have hands-on training for Neglected Tropical Disease Vaccine researchers May 28 – June 7, 2012. See http://www.immunome.org for information. This workshop is linked to the 27th Annual Molecular Biology Summer Workshop at Smith College, June 10 through June 23 and again on July 8 through July 21. A limited number of scholarships will be made available to international applicants of the Smith College summer workshop only, but iCubed and Smith College will work together to provide recipients with a letter to permit foreign applicants to attend both workshops.

• For more information about the Smith College workshop and scholarship, please visit this website.

Speaking Engagements – come hear our latest updates!

1/30 – 1/31
·         3rd Annual Advancing Biologics
·         Munich, Germany
·         Topic of Talk: Regulatory T cell epitopes “Tregitopes” and biologics: A paradigm shifting immunogenicity solution
·         http://www.nextlevelpharma.com/events  
2/27 – 2/28
·       5th Antibody Generation, Engineering, and Design
·       Frankfurt, Germany
·       Topic of Talk: Immunogenicity: The Latest Advances in Reducing the Risk: Deimmunization and Tolerance
·       http://antibody-engineering.com/

3/15 – 3/17
·  CSL Behring’s 2nd Natural Antibody Workshop
·  Bern, Switzerland
·  Topic of Talk: Tregitopes- Overview and MOA

4/17 – 4/19
·  13th Annual Immunogenicity for Biotherapeutics
·  Baltimore, Maryland
·  Topic of Talk: Identifying Host Cell Genome Epitopes and What They Mean for Immunogenicity
·  www.immunogenicityevent.com

5/9 – 5/13
·  8th International Congress on Autoimmunity
·  Granada, Spain
·  Topic of Talk: Tregitopes: Overview and Method of Action
·  http://www2.kenes.com/autoimmunity
We will also be attending AAI, AAPS, and the Global AIDS conference in Washington DC.
And – sign up to get our newsletter online to keep up with our plans!

From: The Providence Journal – Providence, R.I.
Author: Bryan Rourke
Date: Dec 2, 2011, Page: A.1 Local News

Another year passes. Another 100 Rhode Islanders contract HIV, the cause of AIDS. Thursday was World AIDS Day.

Rhode Island officials expressed both concern and hope over improved medications.
“We’re concerned people aren’t protecting themselves against HIV,” said Dr. Karen Tashima, director of Miriam Hospital’s HIV Clinical Trials Group. “Is it that they’re not aware of how serious an HIV infection can be or that they think can just take a pill a day?”
People should maintain precautions, officials say, and increase testing. That can not only curb the virus, they say, but eliminate it. That’s the hope.

“We have something right now that can cure HIV around the world,” said Dr. Annie De Groot, founder and scientific director of Global Alliance to Immunize Against AIDS, based in Providence, and director of the University of Rhode Island’s Institute for Immunology and Informatics. “It’s treatment.” In January, De Groot said, she hopes to prove this in Mali, which she calls “the frontline of HIV.”

Closer to home, HIV persists in Rhode Island. Every year, for the last 10 years, 106 to 124 Rhode Islanders have contracted HIV. “The young guys now, who I call the Facebook generation, may perceive HIV as an older man’s disease,” said Thomas Bertrand, director of AIDS Project RI. “There are generational issues.”

A generation ago, an HIV diagnosis was a death sentence. Now, it’s a long, pill-filled life.
“Because we have such great therapies now, we can confidently tell them you will do well,” Tashima said.

Prevention is preferred. Testing is essential. Of the 1.2 million Americans infected with HIV, 20 percent don’t know it, according to the Centers for Disease Control and Prevention.

AIDS Project RI offers free and fast testing: results in 20 minutes.

Tashima said she hopes for more HIV testing in Rhode Island as a result of the state dropping its written-consent requirement. “The written consent set up a barrier,” Tashima said. “It made it seem like a bigger deal.”

Of the 106 new HIV cases in Rhode Island last year, 6 involved drug users, 13 involved heterosexuals and 54 involved gay men; 33 were of unknown origin. “It’s a persistent challenge,” Bertrand said. “That could be a result of how the doctor asks the question, or the patient’s comfort with the doctor.” Dismissing HIV as a manageable disease, Bertrand said, misses the emotional stigma and the financial expense. HIV, he said, costs $650,000 to treat over the course of an average patient’s life.

Immediate and aggressive treatment, De Groot said, is the answer. She founded Global Alliance to Immunize Against AIDS in 2001. “Every vaccinologist’s dream is to develop the vaccine,” De Groot said. “Why not have that dream?”

That dream, De Groot reports, is fast becoming reality.

De Groot’s organization, which has received $3 million in funding from the National Institutes of Health, has developed four vaccines that “showed promise,” and is working on a fifth. However, De Groot said, the solution to the HIV problem already exists.
“If you treat people the minute they are HIV infected and bring down their virus to zero with current medications, there’s no transmission of HIV,” De Groot said.

This approach was promoted last May in the New England Journal of Medicine. The author of that article, Dr. Myron Cohen, a professor of medicine at the University of North Carolina, and a promoter of that approach, Dr. Julio Montaner, a professor of medicine at the University of British Columbia, are this year’s winners of Global Alliances’s “Hope is a Vaccine Award.”
Applying the approach, De Groot said, simply requires the directing of funding.
“We lack political will,” she said. “There are those who think it’s perhaps more important to spend billions of dollars on defense.”

In January, De Groot said, she intends to approach the government in Mali, where her organization operates a clinic, and seek permission to apply the aggressive testing/treatment approach. “We’re in one of the poorest villages in the world,” De Groot said. “If it can work in Mali, it can work anywhere.”

BY THE NUMBERS
AIDS and HIV in Rhode Island
Here is a statistical picture of AIDS and HIV in 2010.
4,140 to 4,533 Number of people living with HIV and AIDS
106 New HIV cases diagnosed
54% Percentage with male-to-male sex as “risk factor”
30% Percentage of cases with unidentified risk factor
1,486 Number of AIDS deaths, 1990-2010
75% Decline in AIDS cases, 2004-2010
The Providence Journal / Bob Thayer brourke@providencejournal.com (401) 277-7267
Credit: Bryan Rourke, Journal Staff Writer

http://immunome-research.net/journal/index.php/immunome/issue/view/4

Research Article

Julio Montaner, Myron Cohen and Jon Cohen, are Hope is a Vaccine Award Winners, 2011

Access to treatment is the main reason that AIDS-related deaths have tumbled in recent years. That’s something 2011 Hope Is a Vaccine Award winners (International Category), Julio Montaner and Myron Cohen, would have predicted. The two award winners are ardent supporters of the “Treatment as Prevention” approach to ending AIDS, in the absence of an effective vaccine. The approach is strongly supported by recent statistics released by UNAIDS to commemorate World AIDS Day on Dec 1, 2011. UNAIDS also stated “An estimated 700,000 AIDS-related deaths were estimated to have been averted in 2010 alone, due to improved access to care in places like sub-Saharan Africa, which recorded a 20-percent jump in people undergoing treatment between 2009 and 2010.” Also according to UNAIDS, 1.8 million deaths world wide were linked to AIDS in the past year, down from a peak of 2.2 million last seen in 2006.

EpiVax is a major supporter of the GAIA Vaccine Foundation, the organization that names International, National and Local “Hope is a Vaccine Award” winners to commemorate World AIDS Day, December 1st. The Hope is a Vaccine Award highlights the important work done by individuals fighting AIDS and their contributions to improving HIV care for persons living at the margins. The foundation hopes that the award will shed light on the hard work done by courageous advocates, scientists, and policy makers, and will encourage more individuals to be engaged in the fight against HIV/AIDS world wide.

Dr. Myron Cohen is responsible for the publication of a landmark study in the New England Journal earlier this year that showed that treatment with AIDS drugs, known as anti retrovirals (ARV), effectively prevents HIV transmission. In the HIV Prevention Trials Network (HPTN) 052 study, individuals who received ARV treatment early in their infection were at least 96% less likely to transmit the virus to their sexual partners than those who started on drugs later. The reduction in transmission is due to lower amounts of circulating HIV in the infected patient, while they are on ARV treatment.

Dr. Cohen earned the 2011 Hope is a Vaccine award for his dedication to providing a scientific foundation for the Treatment as Prevention. His primary research focus is on transmission and prevention of transmission of HIV, with emphasis on the role played by STD co-infections.  Much of Dr. Cohen’s research has been conducted in resource constrained countries, especially in the African country of Malawi and in the People’s Republic of China. He is currently the J. Herbert Bate Distinguished Professor of Medicine at the University of North Carolina at Chapel Hill.

Dr. Julio Montaner has also been an outspoken advocate of the Treatment as Prevention approach, also known as TasP. He has been a forceful advocate for expanded access to ARVs as early as 2009 and promoted TasP as president of the International AIDS Society and in scientific publications. He is originally from Buenos Aires, Argentina. He is awarded the Hope is a Vaccine Award in honor of his worldwide advocacy for “Treatment as Prevention”. He is a Professor of Medicine at University of British Columbia and is the Director of the BC Centre for Excellence in HIV/AIDS.  He has been a member of the International AIDS Society (IAS) since 1988, and is the IAS past President (2008-2010).

• National Hope is a Vaccine Award 2011: Jon Cohen, journalist, Science

Jon Cohen is a correspondent with Science who has covered HIV/AIDS from every angle – starting with his award-winning report on the epi-center of the epidemic in the former Zaire, and later reports on excursions to report on HIV/AIDS in the former Soviet Republic, Asia, Latin America and the Caribbean. His book entitled Shots in the Dark: The Wayward Search for an AIDS Vaccine (W.W. Norton, 2001) won many awards and inspired a documentary movie. Along the way, he has accumulated an impressive knowledge of the personalities and players in the AIDS Vaccine field and is well known for his insightful reporting on that topic. The National Hope is a Vaccine Award 2010 goes to Jon because of his dedication to the HIV/AIDS chronicle and his commitment to ‘telling the whole story’.

• Local Hope is a Vaccine Award Winner: Paul Loberti, Public Health HIV/AIDS and TB Prevention expert based in Providence, RI

Paul Loberti, MPH, is the Chief Administrator of the Office of HIV/AIDS and Viral Hepatitis at the Rhode Island Department of Health. In this capacity he directs HIV, AIDS and Viral Hepatitis prevention and care efforts for the state. He has been an unfailingly devoted proponent of HIV prevention as a means of addressing the HIV epidemic – leading prevention campaigns in bathhouses among other locations, and has not been recognized previously for his efforts.  He has been at the Rhode Island Department of Health for approximately fifteen years.

For previous Hope is a Vaccine award winners, visit the GAIA Vaccine Foundation website.

Tuesday, September 27, 2011

9:45 am – 6:10 pm

Kiri Room

The Westin Tokyo

1-4-1 Mita Meguro-ku, Tokyo 153-8580 Japan

Speakers:

Annie De Groot M.D.

Director and Professor, Institute of Immunology and Informatics,University of Rhode Island and CEO/CSO EpiVax;

Frances Terry, Immunoinformatics / Bioinformatics Specialist, EpiVax, Inc.

Keizo Yoshida Ph.D., EpiVax Asia

To register for the seminar, contact CMillerIV[at]EpiVax.com or YoshidaKeizo@gmail.com

For more information on Tregitopes, please see this link: http://tinyurl.com/EpiVax-AAPS-Award  and also this link for the original paper: http://tinyurl.com/ASDeGroot-Blood-2008 and here for the relevance to protein medicine: http://tinyurl.com/ASDeGroot-Clin-Immunol-2009

]]> http://www.epivax.com/news/westin-immunogenicity-seminar-september-27-2011-tokyo-japan/feed/ 1 http://www.epivax.com/blog/trogocytosis-not-just-for-trolls/ http://www.epivax.com/blog/trogocytosis-not-just-for-trolls/#comments Tue, 06 Sep 2011 01:01:50 +0000 Anne De Groot http://www.epivax.com/?p=1590 Continue reading →]]> I dunno, I think that Trogocytosis sounds like something that trolls do. But actually, it appears that T cells do this, and in particular, T reg cells do it to antigen presenting cells and to other T cells (See Picirillo, Autoimmunity 2011). What is Trogocytosis? It’s the process by which cells acquire bits of membrane (and whatever else is on it) from other nearby cells. Dendritic cells do it to tumors, and it may be critically important for host defense against cancer. Perhaps more to the point for autoimmunity, both Teff and nTregs can acquire MHC filled with peptides from antigen presenting cells (APCs).

Maybe Trogocytosis is how nTreg cell-contact mediated suppression works. Take a look, if you have a minute, at Clare Allen’s  nice review paper on Tregs – apparently the Tregs that are the most effective down-regulators are the ones with MHC class II (HLA DR) on their surface.

Does any one wonder why some Tregs are armed with HLA DR, or where it comes from? Apparently, 20 to 30% of CD4+CD25high Tregs express HLA-DR (See Clare’s previous paper). Do the HLA DR come from APCs, and are they filled with peptides that then become the target of immune suppression (once the T cell that recognizes the antigen docks on the Treg, then the Treg can exert its effect).

I think it makes sense for Tregs to actively acquire MHC plus peptides from neighboring APCS. That way they can present the MHC and cognate epitope to passing T cells, and directly control their response. Too much inflammation going on? Then arm the Tregs with DR and the corresponding epitope, get the T effectors to dock directly on the Treg, and you have a means of shutting of the T cell responders. This off-switch can be precise, local, and antigen-specific.

Now if we can only capture that concept and turn it into a treatment for autoimmune disease. Perhaps we can use Trogocytosis to turn autoreactive T cells into stone.

What was I doing to keep my mind off Mother Nature during the storm? I was contemplating something far smaller in size. Cricetulus griseus to be exact – or the Chinese hamster. Chinese hamster ovary or CHO cells are the most commonly used cell line to produce therapeutic proteins. Pharmaceutical companies use CHO cells to produce tons of proteins on a global scale. Inevitably, some CHO cell proteins get in the mix. We are beginning to use our tools to determine whether having hamster-derived protein, or “host cell protein” (HCP) in the mix with protein drugs might be good, bad, or indifferent.

Since CHO-derived proteins are usually drugs for human use, they are purified to incredibly high standards and any amount of the HCP in the final product is tiny. But it is well known that CHO proteins are generated during the culture of the protein, and can therefore contaminate the final product. These HCP can potentially generate immune responses in the humans to which the drug is given.

Indeed, in two previous studies (one by Ingerslev et al., on FVIII-deficient patients, prior to and post factor VIII treatment), CHO proteins clearly induced immune responses. Anti-CHO antibodies have even been identified in 54% of individuals who have no history of exposure to protein therapeutics. The significance of these antibodies is unknown, particularly since the HCP against which they are directed is usually also unknown. If, by any chance, that HCP is similar to human (which it may well be, since both are mammals), then there is a slight chance that anti-HCP immune responses might cause problems for the human patient.

The publication of the CHO genome (see Xu X, Nagarajan H et al. in Nat Biotechnol) is a major step forward for many reasons. For one reason, it will be easier to target genes in the CHO genome and turn them on and off. For another, we can begin determining what CHO HCP are in the mix when protein drugs are produced.

Since we don’t yet have 2-D gels to work with, we selected a few highly secreted proteins to illustrate our approach. Once we selected the secreted proteins from the CHO genome, we applied EpiMatrix and ClustiMer, our standard immunogenicity screening tools. The proteins were then scored based on potential immunogenicity (setting aside Tregitopes, which is another chapter of the story).

Long story short? Considering that both humans and hamsters are mammals, the CHO proteins we looked at, that might be secreted (based on the bioinformatics signature) into cell culture supernatant are remarkably unlike human. Some have very few T cell epitopes (red bar in the negative zone) and cannot be expected to generate a very significant immune response, but some have lots of T cell epitopes (score higher than 20 in the graph). That’s not good, if you’re thinking about HCP from the immunogenicity perspective.

CHO Proteins are shown on our standard Immunogenicity Scale. Any score above 20 is potentially immunogenic. Determination of sequence deviation from human homolog would need to be factored into risk assessment.

The good news? HCP potential for immunogenicity can be ranked, like any other protein, with immunoinoformatics tools, and the dominant (highest scoring) epitopes mapped and compared to human.

What does our ability to score CHO HCP and find epitopes mean? Well, right now, we don’t know, and we won’t know until we do some further in vitro studies. But should any of those HCP epitopes be much like human, and added to a drug – or even worse a vaccine (in which case the HCP would be administered with an adjuvant), the result could be autoimmunity . Or, if they are unlike human, and added to a drug, the result might be immunogenicity. Or perhaps the quantities of protein that are left over from CHO culture are so small as to render this hurricane afternoon contemplation completely irrelevant. But somehow I think not.

One thing I do know, is that because we are able and willing to contemplate these things, we may be better off. The trees that fell over during the hurricane were the big, tall, rigid ones. The ones that are still standing are the ones that are more flexible, and can bend in the wind.

Like the trees, we can bend with the wind. The CHO genome is now available. We have the option and perhaps, even the obligation to consider the CHO genome as a source of information for HCP. We now have tools in our hands to answer some critical questions. Is it Human? Is it Hamster? Is it potentially immunogenic?

For more thoughts about CHO and immunogenicity, catch me at one of my upcoming talks. They are posted here. Or write back to me (comment on this blog below) and give me your opinion. I’ve given you mine, and now I’m interested in hearing yours.

I’m getting serious about Thinking Out Loud this fall. And I’d like to get your feedback. Sharing ideas is important, and the work we’re doing – translating ideas into medicines, has a huge impact on human health.

If you want to hear me postulate in person, see the list of conferences scheduled for September here. Or, follow the links in this email back to the blog, and if you want to write me directly, please do that too.

Here are the latest ideas that I’d like to share.

I think that immunogenicity – and tolerance for that matter, is the sum of a set of signals that can be directly linked to protein sequence. Both positive signals (T effector epitopes) and negative signals (T reg epitopes) may be present. The immune system sums the signals and produces a local output. The best analogy is the rheostat – which similarly sums analog signals and produces a single output. Why so sure? Read this for example.

Negative signals are almost as important as positive ones. We’ve come to find that Tregitopes are negative signals (induce regulatory T cells) and the evidence that they are present is solid. We’ve been working away on validating the observation we first published in 2008 for quite a while. Tregitopes definitely impact protein therapeutics, and immunogenicity, and they demand your attention.

T effector epitopes act as positive signals. The good news? They can be predicted using in silico tools with a high degree of accuracy, but which tools you use determine the accuracy of your prediction. If you use off the shelf (on line) tools, you have to take the similarity between HLA pockets into account (see Greenbaum and Sydney, 2011). Proceed with caution! This similarity between HLA pockets means that predicting for a population based on HLA nomenclature based on the assumption that the names of HLA molecules reflect different structure, will lead to over-prediction for some HLA pockets.

Measuring T cell response is an art. I am sure most of you know that, but I think it’s important to emphasize that the phenotype of cells that respond to proteins is important. Simply measuring proliferation – although cheap – is not enough. Tregs proliferate. So do T effectors. Will proliferation assays discriminate and give you an accurate picture of immunogenicity? No they will not.

And finally, my favorite news – T cells talk directly to each other. Have you taught a class recently and noticed that your students are texting to each other rather than raising their hands?  That’s what goes on in the immune system. Sometimes text messages (cytokines) are all that is required, but occassionally the T cells actually pass notes - as in pieces of cell membrane, with antigens included, to each other.

I’m full of ideas and want to hear  your feedback. The results of these discussions and the output of “thinking out loud”  will be available on my blog this fall. Link to my blogs are at the left – including a recent post on ‘naturally deimmunized’ proteins (hirudin). 

These are just a few of the ideas I will be exploring . . .
Follow my blog and talk back to me on line. I look forward to our discussions.

Annie De Groot, M.D. CEO/CSO, EpiVax Inc.
Providence, Rhode Island

Broadest Immune Response from Nasal Spray Vaccine, NIH-Funded Study Finds

(The following is an excerpt from an article published by the National Institute of Allergy and Infectious Diseases on August 16, 2011. Featured in the article is Dr. Daniel Hoft, who collaborates with EpiVax on vaccine research. In addition, Dr. Hoft gave a lecture titled “Romana’s Sign of the Times: Molecular Approaches for Protective T. cruzi Vaccines” during iCubed’s 2010 Vaccine Renaissance Conference.)

‘Children younger than 3 years old receive the same protective antibody response from the recommended two doses of licensed seasonal influenza vaccines regardless of whether the two doses are injected by needle, inhaled through a nasal spray or provided through one dose of each in any order, according to researchers funded by the National Institutes of Health. Doctors usually give young children two matching vaccines, and one goal of the study was to determine whether giving two different types of vaccines works just as well.’ (Read the full article here)