Bespoke Event - Online Conference May 20, 2021 (7)

 

 

"Translatability of current preclinical mouse models, as pertaining to immunotherapy profiling and assessment, is undoubtedly a 'hot topic' these days, and it has been our continuous goal at genOway since 1999."

Our first Bespoke Event, which took place on May 20th in the form of a half-a-day virtual conference, focused on:

  • Revolutionizing PK/PD and efficacy studies in humanized models
  • Assessment of the human immune response to immunomodulators in next-generation HIS mice

More than 290 scientists from 28 countries participated to this event. The scientific presentations included invited speakers from partners, including Crown Bioscience, Aelin Therapeutics, Aarhus University, IGM Biosciences, and Pandion Therapeutics.

 

Prof. Ken Howard, Associate Professor and Head of the Bioengineered Drug Delivery Designs Laboratory, iNANO, at Aarhus University

Physiologically Relevant Mouse Models to Investigate PK & Efficacy of HSA-Based Drugs

Ken presented his work investigating pharmacokinetics and efficacy of HSA-based drugs. Albumin, because of its natural transport properties for endogenous ligands, is broadly used as a drug-delivery cargo. In a recent effort to study bispecific antibodies with tuned FcRn affinity, a new immunocompromised model was developed in an existing double-humanized HSA/hFcRn mouse model. In addition to its relevancy for pharmacodynamics and half-life extension studies of albumin variants, this new model shows no T or B cells, and can grow human tumors upon injection, thus allowing anti-tumor efficacy assessment of bispecifics. Importantly, PBMC need to be co-injected with the tumor cell line and tested compound, which provides an unusual distribution and infiltration of immune cells in the tumor micro environment. This specific point was discussed during Q&A, with Ken mentioning that a reconstituted version of these immunocompromised mice would be a valuable tool for such studies.

 

Dr. Ludovic Bourré, Senior Director, Scientific Engagement, at Crown Bioscience

Human-Specific Immunotherapeutics Evaluation in VISTA & GITR Humanized Mouse Model

Dr. Ludovic Bourré, Senior Director, Scientific Engagement, at Crown Bioscience focused on two humanized mouse models, GITR and VISTA, shown to be valuable tools for the evaluation of human-specific immunotherapeutics. Ludovic showed that each model can bind target-specific antibodies, whereas WT mice cannot. These models can be used as syngeneic recipients for anti-tumor efficacy assessment of mono and combination therapies, including immunophenotyping and analyses of cytokine levels. The importance of humanizing the corresponding ligand(s) to these receptors was discussed, with Ludovic noting that for agonists’ therapeutic evaluation, it is not mandatory, whereas it is an absolute requirement for inflammatory models such as GITR.

See also: hVISTA | hGITR

Dr. Niina Veitonmaki, Head of Biology at Aelin Therapeutics

Pept-ins™, First-in-Class Technology Targeting Broad Disease Areas & High-Value Undruggable Targets

Dr. Niina Veitonmaki, Head of Biology at Aelin Therapeutics, presented its new platform based on Pept-ins™, short peptides selectively driving the aggregation of specific proteins involved in several diseases, to develop novel therapeutics. They underlined the importance of having relevant and physiological models in preclinical drug development. Indeed, this new platform allows for the development of a new category of potential therapeutics that need thorough preclinical validation. As a proof of principle, Niina showed that Vascin Pept-in™ inactivates VEGFR2 while conditionally inducing cytotoxicity in vivo.

Dr. Fabiane Sônego, Innovation Project Manager at genOway

Spotlight: Immunocompetent Humanized Mouse Models for Profiling T-Cell Engagers & Bispecific Antibodies

Fabiane shared recent results, obtained in collaboration with Charles River Laboratories, on a preclinical humanized CTLA-4 mice for in vivo efficacy assessment and tumor-specific immunological memory of ipilimumab therapies. Moreover, they presented examples of two novel bispecific antibodies with improved tumor-targeted immunoreactivity and reduced immune related adverse effects of combination therapies directed against PD1/CTLA-4 and CTLA-4/OX40 blockades, respectively. Finally, Fabiane presented recent data, obtained in collaboration with AstraZeneca, on a preclinical humanized CD3ε mouse model for profiling T-cell engagers and bispecific antibodies.

See also: hCTLA-4 | hPD1/hCTLA4 | hCD3ε

Dr. Poonam Yakundi, Scientist II at IGM Biosciences

Pharmacodynamic Assessment of Bispecific IgM Antibody Using BRGSF-HIS Mice

Poonam shared IGM's latest results on immunodeficient BRGSF mouse model reconstituted with a human immune system (BRGSF-HIS). More specifically, Poonam showed that, compared to other humanized mouse strains, BRGSF-HIS animals boosted with hFLT3 represent valuable models for pharmacodynamic assessment of bispecific IgM antibodies.

See also: BRGSF-HIS

Dr. Kevin Otipody, Senior Director, Immunology, and Dr. Lindsay Edwards, Senior Scientist, at Pandion Therapeutics

Humanized Mouse Models in the Development of PD-1 Agonists

Kevin and Lindsay presented their approach to develop PD-1 agonists, and the importance of humanized mouse models in this process. Their work focuses on developing agonists of the PD1 axis to regulate the immune response (autoimmunity) rather than activating it. In this context, choosing a relevant mouse model is key, as they need to recapitulate the resting and inflammatory stages of autoimmune diseases, and humanized models can be of particular interest. They discussed the pros and cons of different preclinical models, as no perfect model exists, underlining that it is of critical importance to know the advantages and limitations of the models used in order to correctly interpret any data.

See also: hPD-1

Dr. Annie An, Associate Director, and Dr. Dean Campbell, Director, Scientific Engagement, at Crown Bioscience

Engraftment of AML-PDX: Selection of Strains of Immunocompromised Mice Induction of Human Cytokine Release Syndrome in Humanized BRGSF Mice

Annie and Dean presented results obtained in BRGSF immunocompromised mice. Annie focused on the engraftment of AML-PDX in a selection of immunocompromised mice strains, by following tumor growth and infiltration of immune cells. BRGSF presented the most reproducible results, better survival for two out of three AML-PDX models and similar or higher infiltration in tissues. It was discussed that new humanized immunodeficient mice with human cytokines may help further improve AML-PDX disease modeling. Dean then presented data on the induction and characterization of Cytokine Release Syndrome in reconstituted HIS mice. They showed that BRGSF-HIS mice represent a good model to study CRS and the involvement of the myeloid compartment in this process. Indeed, there is a shift in the scientific community to look at the myeloid compartment’s importance in CRS, and HIS mice are now increasingly used to study irAEs.

See also: BRGSF-HIS

Dr. Kader Thiam, Senior Vice-President, Discovery, Preclinical Models and Services at genOway

BRGSF-HIS Mice: A New Model to Assess the Human Immune Response to Immunomodulators

Kader Thiam presented recent published data on BRGS-HIS mice engrafted with matched, paired PDX, demonstrating that these animals predict the responsiveness of patients treated with pembrolizumab. Moreover, they discussed other published data showing that, upon high dose IL-2 treatment, the BRGS-HIS strain mimics the cytokine storm reported in patients undergoing IL-2 immunotherapy. Finally, they briefly disclosed some interesting, ongoing studies in collaboration with CrownBio on BRGSF-HIS mice on OKT3-induced cytokine release syndrome.

See also: BRGSF-HIS