Innovative Development Strategies and Applications for Bispecific Antibodies

The team behind the Next Generation Protein Therapeutics Summit have recently produced an exclusive whitepaper titled "Innovative Development Strategies and Applications for Bispecific Antibodies". Below you will find a brief summary of the whitepaper and download the complete whitepaper now.

Whitepaper Summary:

The phenomenal growth of the bispecific antibody arena has culminated in 60 unique constructs, more than 30 in clinical development, and two on the market as therapeutics for a wide variety of cancer types and numerous diseases/disorders. Bispecific antibodies are specially engineered antibodies which simultaneously bind to two different epitopes on the same antigen or different antigens, increasing selectivity and effectiveness. [1]

The focus in incorporating bispecific antibodies within oncology applications has been in either blocking multiple and redundant signaling pathways involved in oncogenesis or redirecting immune effector cells to be in close proximity to tumor cells. In non-oncology applications, a major developmental effort has gone into blocking pro-inflammatory cytokines.[2, 3]

Despite successes in development there are some critical hurdles to overcome and there is a need for innovation and improvement. Manufacturability issues such as low expression yields and product instability/short half-life have hindered development. Challenges lie in the need for rapid discovery of lead bispecific antibodies with optimal selectivity for their targets, and a need for rapid purification techniques. Adverse effects from immunogenicity, mainly caused by a “cytokine storm,” can stifle clinical trials.[3]

Development efforts have provided some solutions to these hurdles. Researchers at Eli Lily are using mathematical modeling parameters to make predictions about how engineered antibody properties will affect binding to cell surface antigens, ultimately optimizing developability. [4]Another novel strategy involves monitoring target/ligand binding of bispecific antibodies through surface plasmon resonance (SPR), which allows users to view the dynamics of bispecific antibody binding and dissociation events with two targets. [5]

The short half-life of scFv-based bispecific antibodies is a major drawback compared to that of IgG-like bispecific antibodies. Successful half-life extension, and in some cases, recycling, has been achieved by attaching a variety of components: PEG chains [6], human serum albumin, and Fc fragments [1]. In another novel approach, human mesenchymal stromal cells (MSCs) can be genetically modified to produce and secrete bispecific antibodies that accumulate near tumors continuously throughout the lifetime of the patient.[7]

A plethora of unique applications are being investigated for bispecific antibodies. One is in delivery of therapeutic antibodies across the blood-brain barrier for neurological conditions. [8]Another innovative application involves engaging bispecific antibodies to deliver drug, nanoparticle or radiolabel payloads to tumor sites. [1]Bispecific antibody-based immunoassays are being developed for diagnosis of patients with various infectious diseases: SARS, hepatitis B, tuberculosis, as well as E. coli infections. [9]Another application involves tackling the rising threat of antibiotic resistance through specially designed constructs effective against antibiotic resistant bacteria such as Pseudomonas aeruginosa. [10]

This exciting and fast moving arena includes many creative design formats, and innovative solutions for numerous development and manufacturing issues. There are still many unmet needs, but the field is bound to yield many more successes.

Download the Complete Whitepaper

1. Fan, G., et al., Bispecific antibodies and their applications. Journal of Hematology & Oncology, 2015. 8(1): p. 1-14.
2. Spiess, C., Q. Zhai, and P.J. Carter, Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol, 2015. 67(2 Pt A): p. 95-106.
3. Spasevska I, D.M., Klein C, Dumontet C, Advances in Bispecific Antibodies Engineering: Novel Concepts for Immunotherapies. J Blood Disord Transfus 2015. 6(243).
4. Rhoden, J.J., G.L. Dyas, and V.J. Wroblewski, A Modeling and Experimental Investigation of the Effects of Antigen Density, Binding Affinity, and Antigen Expression Ratio on Bispecific Antibody Binding to Cell Surface Targets. J Biol Chem, 2016.
5. Karllson, R., Applications of Surface Plasmon Resonance for Detection of Bispecific Antibody Activity. Biopharm International, 2015. 28(10): p. 38-45.
6. Kontermann, R.E., Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol, 2011. 22(6): p. 868-76.
7. Aliperta, R., et al., Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts. Blood Cancer Journal, 2015. 5: p. e348.
8. Couch, J.A., et al., Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier. Science Translational Medicine, 2013. 5(183): p. 183ra57-183ra57.
9. Byrne, H., et al., A tale of two specificities: bispecific antibodies for therapeutic and diagnostic applications. Trends Biotechnol, 2013. 31(11): p. 621-32.
10. DiGiandomenico, A., et al., A multifunctional bispecific antibody protects against Pseudomonas aeruginosa. Science Translational Medicine, 2014. 6(262): p. 262ra155-262ra155.

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Creating New Pathways for the Development, Translation, and Delivery of Immunotherapies

The team behind the Next Generation Protein Therapeutics Summit have recently produced an exclusive whitepaper titled "Creating New Pathways for the Development, Translation, and Delivery of Immunotherapies". Below you will find a brief summary of the whitepaper and download the complete whitepaper now. 

 Whitepaper Summary:

The last decade has seen substantial growth of immunotherapy treatments for cancer. The new immunotherapies have produced exciting results in terms of response rates to treatment for certain cancers, such as melanoma, which have been refractory to treatment, once substantial metastasis has occurred. The US Food and Drug Administration (FDA) has approved several antibodies against immune checkpoint inhibitors based on the encouraging results in clinical trials. Other types of immune therapies are also being developed which may also be useful in the treatment of cancer.

New antibody/cytokine fusion proteins, anti-CD 137 monoclonal antibodies (mabs) for stimulating cells of the immune system, more refined uses of cytokines in immunotherapy treatments, cancer vaccines, use of genetically engineered T cells to specifically target tumors, new techniques in stimulating the innate immune system and combinations of immunotherapies have great potential for being effective treatment options for cancer treatment in the future.

Challenges, however, remain to perfect these therapies for use in the clinic for cancer treatment. The nature of these challenges are scientific, clinical and regulatory. Scientific challenges include defining the appropriate tumor types for an appropriate immunotherapy, the conditions under which various cells of the immune system would be activated and determining how best to manipulate them to allow for maximum tumor cell destruction, finding better ways to circumvent cancer cell suppression of immune cell responses and using new techniques to prevent or ameliorate the nonspecific injury to normal tissue that can occur as a side effect of immunotherapeutic treatment.

Clinical challenges include ensuring there is adequate quality control in manufacturing process to supply the agent in pure enough form for clinical trials, obtaining enough patients that meet inclusion criteria, designing clinical trials that will yield adequate information to assess the safety and efficacy of the treatment and defining appropriate endpoints for a cancer clinical trial to effectively interpret clinical data gained from the clinical trial.

Regulatory challenges can occur at multiple levels for companies or entities trying to gain FDA approval for their immunotherapy technique or product. These challenges can be at the preclinical level, clinical or manufacturing levels. Adherence to regulations governing Good Laboratory Practices, Good Clinical Practices, and Good Manufacturing Practices can be problematic when trying to take immunological reagents or cellular treatments from the research laboratory to the cancer treatment clinic.

Despite the challenges when conducting research and treatment with immunotherapies, the intense level of research and data being generated with immunotherapies for cancer will ensure that a wide variety of new therapies will be possible in the coming years.

Download the Complete Whitepaper 

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The Next Generation Protein Therapeutics Summit: Earn a complimentary pass as a Guest Blogger!

Earn a complimentary all-access pass to The Next Generation Protein Therapeutics Summit by serving as a Guest Blogger at the event. As a Guest Blogger, you’ll have access to the Next Generation Protein Therapeutics, and the co-located Cell Line Development & Engineering, and Bioconjugates: From Targets to Therapeutics events’ comprehensive agenda attracting the best insights from around the world, right in San Francisco, California in June.

The Next Generation Protein Therapeutics Summit
and the co-located 
Bioconjugates: From Targets to Therapeutics and Cell Line Development & Engineering

June 13 - 15, 2016

Parc 55 Hotel, San Francisco, CA

We are looking for an industry expert with interest in the following topics:

• Speed of discovery and development
• Alternative administration routes
• Potency and payload capacity
• New potential targets in cancer
• Half-life
• Robustness of discovery and preclinical development of bispecific antibodies
• Generation of human bispecific antibodies
• Efficiency of CMC development
• Development of large scale, high yield and manufacturing process

• High-Throughput Platforms for Cell Line Development
• Advances in Host Cell Engineering
• Improving Processes and Product Quality
• Improving Biosimilarity
• Assuring Clonality and Stability
• Innovations in Alternative Expression Systems and Novel Host Cell Lines
• Cell Line Development and Modification for Novel Modalities 
• Genome Editing in CHO cells
• Cell Line Development and Modification for Difficult-to-Express Proteins
• Manufacturing Assessment Strategies
• Understanding CHO Metabolisms

• Intellectual Property and Linker Payloads 
• Progress in Combination Therapies 
• Breakthrough Discoveries and Advances in ADCs
• Analytical and Characterization Strategies 
• Eliminating Heterogeneity: Advancements in Site-Specific Conjugation 
• Innovations in ADC Design and Development
• Regulatory Considerations for ADCs 
• From Discovery to Commercialization: Readiness for Manufacturing & Commercialization
• Perfecting the Chemistry Behind Conjugation 
• Conjugate Vaccines and Novel Conjugate Technologies

...and who would like to learn more about protein therapeutics!

The premise is to provide protein therapeutics related articles, whitepapers, and overall original content with a strong focus on the whole protein engineering & design industry.

What You get is:

• FREE pass to the conference (valued up to $2,999.00);
• Access to extensive social learning activities;
• Exclusive admission to a networking community in the industry of your interest!

You also have a chance to GAIN exposure through our blog with over 2000 unique visitors monthly and more than 20 related LinkedIn groups with over 65,000 subscribers combined!

Learn more about the The Next Generation Protein Therapeutics Summit event by visiting our website.

Interested & want to learn more about this opportunity? Please contact Ksenia Newton at knewton@iirusa.com. Feel free to share your short biography, links to your blog or writing samples, along with a few sentences about why we should choose you to become the Guest Blogger for the Next Generation Protein Therapeutics Summit 2016!

We hope to have you join us in San Francisco!

* Guest Bloggers are responsible for their own travel and lodging.

* All content is subject to IBC approval.

Stay tuned: 

@futurebiopharma

#ProteinSummit

Visit the website: http://bit.ly/208zLVP

Future of Biopharma Blog http://futurebiopharma.blogspot.com/

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Peptides for CNS and Alzheimer's Disease Therapy

Exclusive TIDES 2016 interview with Dieter Willbold, Ph.D., Director, ICS-6 Structural Biochemistry, Forschungszentrum Jülich, Germany. Dr. Willbold gives us some exclusive insights into the topics he will be addressing onstage at the 18th annual TIDES in just 4 weeks time. Don't miss out on this record setting meeting; join over 800 global attendees over 4 days full of insights and learnings. Register for TIDES by Friday, 4/15 and save $300 - Use the code B16180BLOG.


Dr. Willbold Interview: 

What current challenges are you facing for advancing your promising peptide for Alzheimer's disease through clinical trials?

Our main focus at the moment is to finish all the necessary preclinical tox and safety tests in order to soon get permission for a clinical phase I study with our drug candidate.

One challenge for developing therapeutics like ours that target specific aggregate species, lies in the lack of suitable analytics to measure target engagement, because most methods don't differentiate between different aggregate sizes. In addition to cognitive behavioral tests, we ourselves have therefore developed novel methods to measure efficacy and target engagement .e.g. QIAD (short for quantitative determination of interference with aggregate size distribution; Brener et al., Scientific Reports 2015), which measures Abeta oligomer elimination efficiency.


What are the advantages of peptide therapeutics over small molecules, antibodies and other protein therapeutics?

Small molecules often lack specificity, and this can lead to serious side effects and autoimmune responses. On the other hand protein-based therapeutics like antibodies possess high target selectivity and are made of natural components, but they are very big and expensive molecules. They often suffer from low oral bioavailability.

Small peptides can offer the best of both worlds in some respects: They are more target specific than small molecules but easier to produce than protein based drugs. Our drug candidate is made solely from D-enantiomeric amino acid residues and has surprisingly good oral bioavailability.


Where do you see innovation happening in the peptide field over the next 5 years?

Innovation will certainly happen in the production of peptides (cost reduction) and in the formulation of peptides (increase oral bioavailability).

______________________________________________________

Reserve your seat today to attend TIDES 2016 in Long Beach, CA and hear Dr. Willbold deliver a live presentation "Efficiency and Oral Bioavailability of Abeta Oligomer Directed D-Enantiomeric Peptides Developed for Therapy of Alzheimer's Disease", where he will delve into small soluble Abeta oligomers are suspected to be the major toxic species responsible for development and progression of Alzheimer's disease (AD). We developed highly potent D-enantiomeric peptide compounds that specifically eliminate Abeta oligomers and improve cognitive performance and stop or slow down neurodegeneration of AD transgenic mice. Data on stability and oral bioavailability clearly support the superiority of D-peptides over L-peptides.

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Exclusive Interview with Dr. Bruce Riser, CEO, BLR-Bio, LLC

IBC's 18th Annual TIDES is the industry's #1 forum for oligonucleotide and peptide leaders to build successful partnerships and accelerate products from early discovery through late-stage development and commercialization. The TIDES team recently talked to Bruce L. Riser, Ph.D., CEO, BLR-Bio, LLC for an exclusive interview that delves into the topics he plans to discuss at the upcoming Oligonucleotide and Peptide Therapeutics event in Long Beach, CA.

What are the biggest challenges of bringing new agents with novel targets to the market?

BR: There are really two big challenges when bringing new agents with novel targets to the market. First, many investors and potential partners are not familiar with the target, or they do not have the comfort that exists with an established target. Second, there can be misperceptions in the scientific community and in the biopharmaceutical industry where an agent is associated with another type of development creating a negative halo. On the first challenge, it is easy to see a proven target and to line up, jumping on the bandwagon with others trying to either win the race to launch first or to attempt to find a niche in an already established area. The problem of course is that lining up with everyone else does not provide the opportunity to develop and launch a true breakthrough therapy that can change the treatment paradigms and have a breakthrough impact on peoples' lives. Instead, investors and companies that line up for the established target often find they are trailing others to the market and are never able to successfully establish themselves in the market. It really takes a visionary to see the potential of a new target and have the insight and strength to invest in it. The second challenge, dealing with miss-associations of a novel therapy with other developments can be truly vexing. Our peptides target the novel CCN signaling pathway, leveraging the unique qualities of CCN3 to target the control of ECM changes in response to injury, blocking fibrosis and creating an environment for re-establishment of complete tissue homeostasis. By creating peptide libraries and conducting diverse in vitro and in vivo screens we have identified specific regions with the CCN3 protein responsible for blocking single, or multiple, pathways to fibroblast and cancer growth, and fibrosis formation. Unlike other products such as antibodies directed against the pro-fibrotic CCN2, that appear to partially block a single pathway, our novel therapy regulates vs. simply blocking, thus allowing reestablishment of the body's healthy equilibrium.

With several peptide products in the pipeline in preclinical development and a wide range of possible disease applications, how have you selected your lead indication target(s)?

BR: Having several products covering a wide variety of diseases is great and choosing lead indications to pursue is a wonderful challenge to have. In reality, the two lead indications that we have chosen to pursue have as much to do with the research that we have done with my team as it does the extreme health care need. My long background in academia, clinical nephrology/public health, and pharmaceutical drug R&D has driven the way we do drug discovery at BLR Bio. First, working to clearly understand the pathways to disease before selecting a target, and trying not to get caught up by targets in vogue. Then, testing our peptides in multiple related diseases before moving into the clinic. Our pipeline was created out of our long-term interest in fibrosis and the extracellular matrix in biology and disease, particularly in renal fibrosis as a complication of diabetes an area of great medical need. This has led to the selection of diabetic nephropathy as a main target for one of our lead products. Since our target, and the peptide inhibitor of our target, are involved in many other forms of fibrosis and other disease involving the miss-regulation of matricellular signaling, this creates other exciting therapeutic indications down the road. These include NASH, IPF, MD, and scleroderma to name a few.

I began my career in cancer research, and we know now that the extracellular matrix and matricellular signaling proteins such as the CCNs are critical also in the formation and resolution of tumors. The pro-fibrotic CCNs, CCN2 and CCN4 in particular have been shown to be important for the establishment and likely invasion and metastases in numerous tumors. The opportunity to use CCN3-based therapy to, not only halt the cancer, but also to target the microenvironment is an exciting one. Our company is particularly excited about the potential in pancreatic cancer. We have an established relationship with thought leaders in the cancer field and are moving forward with development work, partnering with some of these world experts. To add to the excitement of the therapies, our company also is developing a diagnostic/theranostic based on the same technology platform. It holds the promise of either stand-alone or companion diagnostics for development.

What are the key advantages of peptide therapeutics over small molecules, antibodies and other protein therapeutics?

BR: As you know, peptide-based drugs are one of the most rapidly growing areas in therapeutic development. More than 100 peptide-based drugs are on the market with several effective in cancer treatment. There is good reason for this. In size, falling between small molecule drugs and "biologics", they have many of the benefits of both while shedding many of the deficiencies. For example, because of their small size they gain many delivery benefits over biologics. First, better penetration of tissue at the site of action. This is crucial in fibrotic disease and cancer where there is a very strong barrier to penetration. Second, it allows for many more delivery options, including oral formulation. The earlier assumption of poor metabolic stability of peptides has just not proven to be the case. Although there is often rapid clearance from circulation, the previous assumptions about required PK by classic definition has also proven to be not relevant, since a specific and sustained biological activity at the target receptor is characteristic of many peptides. Unlike small molecules they are based on sequences that have evolved to react with specific receptors and often at very low concentrations. This results in very low off target effects. Last, since they can be chemically synthesized the ease and cost to manufacture are more nearly like that of small molecules. The majority of approved peptides are in the 15 amino acids (aa) range or smaller, and they treat a broad range of diseases.

How do you see academia and industry collaborating in the future to advance promising peptide therapeutics into commercially viable products?

BR: First, we think that academia will play a significant role in the creation of new peptide-based therapies in the future. Since the last decade has seen a decline in the number of newly approved drugs from large pharma, and recently there has been a strong trend for these same companies to dramatically reduce their discovery effort, this creates a large opportunity for novel peptide therapies and academic-initiated translational research. This does not necessarily mean that the new paradigm will be that large strategic companies will license early stage assets directly from Universities. Rather, we anticipate that the most promising discoveries will lead to the creation of start-up companies and the building of defendable IP. Then, large pharmaceuticals will court these start-ups as they progress to become true biotechnology companies with completion of phase I, phase II clinical trials or beyond. We think that the best of these emerging biotech companies will then expand their ability to do discovery and early stage development. They will also be able to clearly evaluate and in-license additional opportunities in academia. These are exactly the skills now lacking in big pharma. These successful discovery biotech's will become the future pipelines for drugs that will go to the mid and large pharma companies centered on late development and marketing. I envision BLR Bio as becoming one of these discovery companies able to contribute significantly to filling this gap.

Want to hear more from Dr. Riser? Join him this May in Long Beach, CA for the 18th annual TIDES - Save $300 when you register using the code B16180BLOG100. Click here to register. 

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Protein Aggregation: The Black Coffee of Drug Discovery

By Scott Wallask

Conference Producer, IBC Life Sciences

I don’t drink coffee. I have had less than 10 cups in my entire life, and the last one I sampled was so terrible I dumped it down a storm drain in the street.

Part of my reason for not liking coffee is there are too many choices. Years ago, my wife’s parents – who are big coffee drinkers – took a road trip to visit us and asked that we grab them some coffee for their stay.

My wife and I asked what kind of coffee they wanted, and we got the good old response, “Oh, any kind is fine.”

My wife doesn’t drink coffee, either (so much for opposites attracting), so my in-laws were quite disappointed when they arrived to find instant coffee waiting for them. My wife and I had no idea what we were buying.

So I sympathize with protein researchers who may sense trouble brewing when they have to choose among a varied selection of instruments and technologies designed to analyze aggregation levels in their drug products.

Protein aggregation seems like black coffee to me: It’s not sweet and you’ve got to be tough to handle it. But minimizing protein aggregation is an effort taking place throughout the drug discovery pipeline, from early research through formulation, all the way to the patient. Technology is a valuable aid when you’re doing aggregation-themed work on the molecular level.

So I’m happy to see so much interest in our technology sessions at IBC’s upcoming Protein Aggregation, Stability & Solubility conference, which takes place June 4-6, 2014, in downtown San Francisco.

One of the highlights of the program for me is a panel discussion with a simple mission: Explore the pros and cons of various tools used to measure aggregation. Our panelists will likely hit upon field-flow fractionation, fluorescence spectroscopy, chromatography, transmission electron microscopy, light-scattering techniques, and ultra-centrifugation — along with any other technologies our audience asks about.

The event also features the following individual presentations about analytical and particle characterization technologies:

• ·  Protein Aggregation and Emerging Tools to Support Development and Characterization (presenter from Gilead Sciences, Inc.)
• ·  New Orthogonal Methods to Test Biopharmaceutical Solutions for the Presence of Aggregates and Particulate Matter (University of Geneva)
• ·  Methods for the Characterization of Biotherapeutic Aggregates (Pfizer, Inc.)
• ·  Light-Scattering Toolbox for Predicting and Characterizing Aggregation (Wyatt Technology Group)
• ·  Use of Solution Nuclear Magnetic Resonance to Identify Site-Specific Structural Changes in Proteins that Precede Aggregation (University of Kansas)

We’d love to see you at the conference, which is the one largest ever dedicated to protein aggregation concerns.

P.S. If you find a coffee flavor you think I’ll like, swing by registration at the event and let me know.

You can find more information on the Protein Aggregation, Stability & Solubility conference here. Register now and save 20%. Use discount code D14200BLOG.

Follow Scott on Twitter @Scott_biopharma

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Attend the #1 Forum for Scientific Exchange in Antibody Engineering & Therapeutics

Accelerate your antibody research by joining us at IBC's Antibody Engineering & Therapeutics meeting, taking place December 8-12, 2013 in Huntington Beach, CA. Join top antibody researchers from across the globe at the #1 forum for academia and industry to connect for scientific exchange in antibody engineering & therapeutics, immunobiology and next-generation binders.

Our keynotes this year offer the latest advances in systems biology and computation design for protein therapeutics. New session topics this year cover the latest developments in antibodies in cardiometabolic medicine, polyreactive antibodies, knowledge-based design and effects of antibody gene variation and usage on antibody response.

New to this conference? Preview three complimentary past presentations from our 2012 event:

• - Exploiting light chain diversity to create a fully human bispecific IgG platform technology
• Nicolas Fischer, Ph.D., Head of Research, Novimmune, Switzerland
• - Improved antibody therapies for the treatment of Clostridium difficile infection
• David P. Humphreys, Ph.D., Director, Antibody Biology, UCB Pharma, United Kingdom
• - Multi-epitopic anti-EGFR antibodies: enhancing surface downregulation by clustering
• K. Dane Wittrup, Ph.D., Professor, Massachusetts Institute of Technology

Download the past presentations here.

Antibody Engineering and Therapeutics will take place December 8-12, 2013, in Huntington Beach, California. If you’d like to know more about the event, download the agenda. If you’d like to join us, as a member of this LinkedIn group, you can save 20% off the starndard rate when you register to join us and mention code XD13172BLOGJP.*

Have any questions? Feel free to reach out to Jennifer Pereira at jpereira@iirusa.com.

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