Genetic Engineering & Biotechnology News

JUL 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.

Issue link: https://gen.epubxp.com/i/996074

Contents of this Issue

Navigation

Page 26 of 33

GENengnews.com | Genetic Engineering & Biotechnology News | JULY 2018 | 25 Dr. Chen's motivation for creating this con- struct was to eliminate the risk of CD19 anti- gen escape. Her approach involved introduc- ing an additional scFv, one targeting CD20, another biomarker of B-cell cancers. This way, any reemerging CD19-negative cancerous tis- sue could still be targeted—and killed—with- out the patient having to go through another, separate round of CAR T-cell therapy. Although TanCARs are of demonstrat- ed efficacy, they have a built-in weakness: they keep their scFvs close together. When the scFvs are multiplexed, they tend to ag- gregate with one another; therefore, scFv- based CAR T-cells can aggregate and lead to CAR CD3 domain phosphorylation, ton- ic T-cell activation, and T-cell exhaustion. To avoid such problems, some developers are constructing non-scFv-based CARs us- ing nanobodies. Exploring NanoCAR Options Nanobodies are composed of one heavy- chain variable domain from a TAA-targeting full-length antibody. Nanobodies can be used on their own because they contain all three complementary determining regions required to bind with an antigenic epitope. Nanobodies can also be incorporated into a modified TanCAR format. For example, tandem nanobodies may replace a bispecific CAR's tandem scFvs. This approach, which goes by the name nanoCAR, is being explored in the labora- tory of Bart Vandekerckhove, M.D., Ph.D., a professor of clinical chemistry, microbiology, and immunology at the University of Ghent and a group leader at Cancer Research In- stitute Ghent. According to Dr. Vandekerck- hove and colleagues, nanoCAR technology can generate CAR T cells that evenly dis- tribute two nanobodies and are therefore capable of simultaneously stimulating two cancer-killing pathways. Using nanobodies rather than scFv- based CARs or bsAbs may present several advantages: • First, nanobodies are so small they do not interact or overlap with each other, allowing them to be built upon one another to form multitarget therapeutics while avoiding the common side effects of scFv aggregation. • Second, mouse-made nanobodies contain a human-like V H domain, allowing them to be weakly immunogenic compared with mouse or humanized scFv- or IgG-based therapeutics. • Third, recent clinical trial data has shown that nanobody-based therapeutics develop minimal antidrug antibodies compared with other common forms of antibody therapeutics. • Fourth, and most important, mono- meric nanobody-based CARs show almost identical efficacy as scFv-based CARs targeting the same TAA in clinical trials. A recent publication from the Vandekerck- hove team highlights the strong efficacy of a nanoCAR that targets both CD20 and Her2. To construct this nanoCAR, which was based on a previously generated scFv CAR target- ing the same antigens, the team selectively re- placed the two scFvs with nanobodies. The nanoCAR was able to selectively bind to either or both antigens and elicit a T-cell re- sponse equivalent to that of its TanCAR pre- decessor. Unfortunately, the team has yet to generate a bispecific nanobody CAR targeting the same cell type; however, it may be only a matter of time before this format is generated and tested in the clinic. What remains clear is that CAR T-cell therapeutics are only at the beginning of charge into the immuno-oncolo- gy scene. If their potential curative powers are realized, these therapeutics stand to benefit a great many cancer patients. High-Throughput Developability Assessment of Therapeutic Antibody Candidates in Discovery Stage The stability of a candidate drug-protein is critical to the success or failure of its development as a viable drug. Low stability could adversely impact production consistency, shipping and handling excursions, and long-term storage. Developability assessments are becoming an increasingly important criterion to mitigate this risk. The conventional approach is to perform the developability assessment on the final few shortlisted candidates at the mid-to-late stage of drug development. At Aragen, we have moved the developability assessment into the discovery phase during antibody screening, accelerating the candidate selection process. Integration of the Uncle platform into our process was essential for early assessments due to its small sample requirements and rapid analysis time. In this study, we show that humanized antibody candidates of a murine monoclonal antibody differ in their thermal melting and thermal aggregation profiles due to differences in the stability of the Fab domain (that carries the target binding residues) because of the humanization process. Destabilization of the Fab domain or lower aggregation onset can lead to problems later during production, shipment, or storage. Assessment of thermal stability and aggregation potential can be an important tool for early selection of viable drug candidates. Analysis during antibody screening (discovery stage) and clone selection (early process development stage) can significantly reduce the time and cost of downstream manufacturing. A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelists. Free Registration! www.GENengnews.com/UNcle View It Now! On Demand DURATION: 60 minutes COST: Complimentary Speakers Jackie Kennedy-Wilde Scientist Aragen Bioscience Dina Finan, Ph.D. Product Manager Unchained Labs Produced with support from Webinars Translational Medicine Samantha Zaroff, Ph.D., is a technical writer and marketing specialist at GenScript Biotech, a provider of life sciences research products and services. The GenScript portfolio encompasses gene synthesis and molecular biology, peptide synthesis, protein expression and engineering, custom antibody development and engineering, in vitro/in vivo pharmacology, as well catalog products for research. Web site: www.genscript.com.

Articles in this issue

Links on this page

Archives of this issue

view archives of Genetic Engineering & Biotechnology News - JUL 2018