Knowledge Library

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and gastric carcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to adverse drug effects.

This webcast will present new work showing that the vast majority of such alterations retain the extracellular domain (ECD), potentially enabling highly selective targeting of the FGFR2 ECD using biotherapeutics.

To improve on the activity of traditional bivalent monotopic antibodies, the Sellers lab systematically generated biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, and identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions.

These antibodies robustly blocked proliferation and colony formation in FGFR2-fusion driven cholangiocarcinoma and demonstrated robust in vivo anti-tumour activity. In vivo activity was marked by significant antibody-mediated downregulation of FGFR2 and in turn this was associated with robust lysosomal internalization enacted by the two biparatopics. In vitro, the biparatopic antibodies demonstrated activity against FGFR inhibitor resistant alleles of FGFR2. The internalization properties of the antibodies also make them suitable for exploration as antibody-drug conjugates

CAR-T therapy can be a highly effective treatment for certain blood cancers such as acute myeloid leukemia (AML), but the mechanisms underlying productive CAR-T cell/tumor interactions are only beginning to be understood. Recent work has demonstrated that productive interactions can be influenced by the density of the target antigen on the tumor cell, stability of the CAR molecule itself, and additional antigen-independent and antigen-regulated interactions mediated by adhesion molecules. The sum total of the T-cell interaction with an antigen-bearing target cell is known as avidity.

Watch this webinar from Marcela Maus to learn about novel CARs and the use of avidity measurements to understand and enhance productive CAR-T cell interactions with both liquid and solid tumors.

Liquid and solid tumors differ in their interactions with CAR T cells and it is important to understand the critical factors associated with tumor escape mechanisms. In this webinar, Dr. Rebecca Larson presented her work on “Loss of IFNγR signaling and downstream adhesion confers resistance to CAR T cell cytotoxicity in solid but not liquid tumors” in Nature, and suggests that enhancing binding interactions between T cells may yield improved responses in solid tumors. Learn how cell avidity measurements can improve CAR T cell response in solid tumors by identifying important evasion mechanism.

B-cell maturation antigen (BCMA) is a potential target antigen in multiple myeloma due to its highly selective expression in malignant plasma cells. BCMA-targeted CAR T-cell therapy has been proven to be effective in patients with multiple myeloma. Despite that complete remission level reaching around 60-86%, a subset of patients still experience tumor relapse. Tumor escape due to low antigen density and limited efficiency in single-targeting BCMA CAR. In this webinar, Dr. Maria Themeli showed how to overcome low antigen density and improve CAR-T cell persistence with multi-targeting and co-stimulation through increasing synaptic avidity with the z-Movi.

NK cells serve as a potential immunotherapeutic tool due to their innate ability to kill cancer cells. They play a crucial role in cancer prevention by providing immune surveillance, making them attractive candidates for immunotherapeutic tool. However, quite often NK cell can fail to recognize and eradicate residual cancer cells, resulting in cancer relapse and lower chance of survival. In this webinar, Prof. Mark Lowdell, Chief Scientific Officer of INmune Bio, Inc. discussed how primed NK cells become effective against resistant tumor cells, and how cell avidity measurements were used to depict a stronger binding of primed NK cells, resulting in improved tumor cell killing.

Multiple myeloma is a cancer derived from malignant plasma cells. Conventional mono-targeting CAR T-cell therapies targeting BCMA have yielded remission in treated patients, however, a large proportion relapses due to BCMA antigen escape as a result of low antigen density. The development for effective CAR T-cell therapy with long-term remission is needed.

Learn from Prof. de Larrea how expressing two CARs on a single cell enhances the strength of CAR T-cell/target cell interactions, prevents BCMA escape-driven relapse, and how cell avidity measurements contributed to their findings in this webinar.

TCR T cell therapy is a powerful tool that can redirect patients’ immune cells to target cancer cells. Conventional assays such as affinity measured by SPR do not always correlate with in vivo results, so the selected candidates might turn out not to be the best one. Our cell avidity expert, Dr. Will Singleterry, will present the insights cell avidity experiments provided for the team of Dr. Nathalie Rufer at University of Lausanne in this webinar.

Bispecifc antibodies (bsAb) are molecules that can steer immune cells, such as T cells, NK cells, towards cancer cells. They facilitate the formation of the immunological synapses (IS), which are key driver of downstream T cell response. In this webinar, our principal scientist will show how cell avidity measures the effectiveness of the events during IS formation, and allow researchers to rank and select the best candidates.

CAR-T cell therapy has increased in its popularity due to its robust nature and being MHC-independent. In this webinar, Dr. Rogier Reijmers, Principal Scientist at LUMICKS, will present several case studies and demonstrate how measuring Cell Avidity provides new insights by providing a more complete and physiologically relevant picture of the interaction between cells and their targets.

Recent work using cell avidity measurements by the Gottschalk lab at St. Jude Children’s Research Hospital (published in Nature Biotechnology) sought to tune CAR synapses in NK cells by adding an intracellular scaffolding protein binding site to the CAR called the PDZ binding motif.

Commercial CAR-T therapies still suffer from severe limitations, as majority of patients fail to achieve complete response and ultimately relapse.

Watch this Webinar to discover Prof. Marco Ruella’s team have adopted a novel CAR-T avidity screening method to improve safety and exhaustion profile, leading to 100% clinical response in a phase I trial.

Acute myeloid leukemia (AML) continues to be an unmet clinical need for both adult and pediatric patients. Although CAR-T cell therapy has demonstrated substantial therapeutic potential, further advancements are necessary to achieve safe and lasting disease remission. In this webinar, CAR-CIK cell pioneer Dr. Sarah Tettamanti, from the Tettamnti foundation in Milan, Italy (alongside our Lead Product Manager, Shira Segal, at LUMICKS) discuss how Cell avidity was used to generate an additional layer of information to understand the mechanism of action and enhance decision-making on identifying the most efficacious candidates whilst limiting toxicity to healthy cells.

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Mechanistic issues limit the effectiveness of many current cancer-targeting antibody therapies, with monospecific antibodies often hindered by receptor dimerization and activation. Biparatopic antibodies, which bind to two unique non-overlapping epitopes, offer a promising solution with stronger binding, more potent antagonism, and higher specificity.

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Next generation chimeric antigen receptor (CAR) T-cell therapies hold promise in providing a curative solution for solid tumors. Nonetheless, the significant clinical hurdle of on-target off-tumor toxicity (OTOT) remains a major downside to the advancement of CAR T-cell therapies.

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Interestingly, 8 out of 10 CAR T lead candidates fail after preclinical development. This suggests that current preclinical in vitro assays insufficiently predictive. This status quo could worsen as the field moves into tackling more challenging targets such as solid tumors, which require more sophisticated next generation designs like dual-targeting, logic-gating or BiTE-secreting CARs. However, implementing Cell Avidity analysis at an early stage in the drug development process can help to identify superior lead candidates and improve (pre)clinical correlation, as shown by this study.

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Identifying effective immunotherapeutic treatment strategies for multiple myeloma that also mitigate relapse often requires tedious and time-consuming validations, such as cell-killing assays and in vivo engraftments. We show that intercellular binding strength (cell avidity), measured by the z-Movi® Cell Avidity Analyzer, quickly predicts CAR T-cell efficacies that correlate with treatment outcomes in vivo.

T cell receptor (TCR) -based cancer immunotherapy has the potential to become a powerful approach to treat solid tumors, such as melanoma. However, conventional methods that validate the effectiveness of TCR transduced T cells are often inconsistent with functional assays or are tedious to perform. In this application note, we show how the z-Movi® Cell Avidity Analyzer reliably and quickly identifies functionally optimal TCR-engineered T cells targeting melanoma cell lines based on cell–cell interaction strength (cellular avidity).

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T cells play a pivotal role in tumor immunosurveillance. Multispecific cell engagers (CEs) have been adopted in the field of immuno-oncology to redirect T cells toward cancer cells, thereby unleashing the anti-tumor potential of the patient’s immune system. CE-mediated cell binding induces T cell activation and the formation of an immunological synapse, which is a prerequisite for effective tumor cell lysis.

The strength of the initial binding events between a T cell and a tumor cell dictates the efficiency of the anti-tumor response. Assessing cell avidity, i.e. the total intercellular interaction strength between two cells, gives crucial insights into the efficacy of CEs as anti-tumor therapeutic agents.

Here, we deploy LUMICKS’ high throughput avidity measurement (HTAM) technology to measure CE-induced cell avidity in a high throughput manner. We demonstrate the assay performance characteristics, i.e. specificity, precision, and range, via CE titration experiments in the context of a Jurkat T cell model system. We find that the HTAM CA assay is suitable for candidate screening in high throughput, with high sensitivity and precision.

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