Genetic Engineering & Biotechnology News

AUG 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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10 | AUGUST 2018 | Genetic Engineering & Biotechnology News | GENengnews.com Epitope Mapping Orients Immune Interventions Continued from page 1 be prioritized. The company uses a normal tissue atlas screen to ascertain if the epitope is being presented elsewhere to help determine the possibility of off-target effects. Approximately 70–80% of peptides are already detected, so only incremental improvements are expected as instru- ments evolve. The big advance will occur once current clini- cal trials data are synthesized. The first generation of cancer immunotherapies was generated primarily through predic- tive algorithms. The next generation will have more direct evidence along with a greater understanding of the synergies that are required for a complete immune response to occur. "Once we sort this out in oncology, the same approach can be applied to other areas in which the immune system is involved, including diseases that do receive as much invest- ment. Cancer may enable the better use of the host immune system across the board. It is a golden age for an immunolo- gist," added Dr. Paramithiotis. Bispecific Architectures Combining binding specificities toward two distinct epitopes into a single molecule can greatly enhance the immunotherapeutic properties of monoclonal antibodies (mAbs). Most cancer targets currently pursued by anti- body therapy developers are tumor-associated, not tumor- specific, antigens. According to Changshou Gao, Ph.D., senior director and fellow, Yariv Mazor, Ph.D., senior scientist, and Nazzareno Dimasi, Ph.D., associate director, MedImmune, binding epi- topes and affinities are two critical parameters determining antibody functions. Different bispecific architectures allow maximization of the additive functions of bispecific antibod- ies (bsAbs) while maintaining the potency of individual an- tibodies; no one bispecific architecture format fits all. The mechanism of action, capability to concurrently engage two different targets or two different epitopes on the same target, and the synergistic potential to improve efficacy should drive architecture choice. Manipulation of affinity, avidity, valency, and architec- ture of bispecific therapeutics will provide opportunities that not only target double-antigen positive tumor cells over single-antigen positive normal tissues, but also selectively engage the highly upregulated antigens in tumor cells. This could lead to improved target selectivity, restricted escape mechanisms, reduced normal tissue toxicity, and improved therapeutic index. The interplay of factors influencing target selectivity is not well understood and often overlooked. MedImmune recently showed in vivo that dual targeting alone was not sufficient to endow selective tumor targeting abilities, and reported the pivotal roles played by the affinity of the individual arms, overall avidity, and format valence in the capacity of a bsAb to promote selective tumor targeting. In the study, the collective role of affinity, avidity, and format valence in the capacity of monovalent and bivalent bsAbs targeting the clinically validated EGFR and HER2 receptors was systemically interrogated to promote selective tumor targeting under physiological conditions. The study used a dual-flank tumor xenograft mouse model system that carried a double-positive target tumor that was positive for EGFR and HER2 antigens on one flank and an isogenic HER2-knockout, single-positive tu- mor as normal tissue on the opposite flank. This system allowed the study to demonstrate that tumor-targeting se- lectivity is clearly influenced by the intrinsic affinity of the individual binding arms. The affinity modulation of monovalent bsAb's individual arms could significantly limit normal tissue targeting without impairing the bsAb's potency against the targeted tumor. An increase in binding site valence has a detrimental effect on the ability of bsAbs to endow selective tumor targeting abilities. These findings provide new opportunities for the use of affinity-modulated monovalent bsAbs in cancer therapy, as they facilitate the recruitment of a broader set of target antigens, previously considered unattractive for therapeutic applications due to comparable densities to those found on normal healthy cells. Viral Immunotherapy The bispecific approach is also being used to tackle some of the inherent challenges in viral immunotherapy. mAbs have a good safety profile and are highly specific. In addition, a protein or another molecule that is part of the pathogen, which is present only during an active infection, is typically targeted, thus lowering the risk of off-target effects. Development and production costs are current barriers. If a cold chain and intravenous injection are required, deliv- ery can be an issue, too—especially for types of viral infec- tions that tend to occur in resource-limited settings. These settings can also impact return on investment. Historically, the government has sponsored development projects with smaller biotech firms, government laboratories, or academ- ic laboratories. Viral immunotherapy is not as advanced as cancer im- munotherapy. An emerging theme is targeting multiple epit- opes simultaneously to provide more arms of attack and to mitigate against the risk of viral escape. mAbs can be mixed into a cocktail; alternatively, multiple variable domains can be engineered into a bsAb. "We work on Ebola and want to increase efficacy with a single therapeutic agent. Bispecific antibody engineering al- lows multiepitope targeting. Many viral antibodies are lim- ited in breadth to one or two members of a viral family; one goal is to provide broad protection against an entire families of viruses," explained Jonathan R. Lai, Ph.D., professor of biochemistry, Albert Einstein College of Medicine. "The concept of targeting the host and the virus is intrigu- ing. All viruses tend to need some type of host receptor to activate the viral machinery that allows the virus to gain cel- lular entry. This can often be the virus' Achilles' heel. If the interaction between the host and the virus is interrupted at that particular site, then you can have a broadly active thera- peutic. Some of these host–receptor interactions occur only in the intercellular compartment, so methods are being explored Drug Discovery At the University of New Mexico, Bridget S. Wilson, Ph.D., an authority on cell signaling, leads a scientific team that brings state-of-the-art imaging, refined quantitative measures, and computational approaches to the study of authentic allergens and how they crosslink and activate human receptors.

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