Complete cell-cell binding characterization
Steer receptor binding to overcome cell therapy exhaustion, improve potency, minimize OTOT, and refine binding sensitivity to overcome immune escape.
Part of:
Why Cell Avidity?
Keeping up with the complexity of binding mechanisms
Many immunotherapies adapt to solve the field’s most pressing issues (an intricate balance between persistence, potency, and safety) by integrating multiple signaling mechanisms and engaging with more than one target in parallel (e.g., logic-gated CAR T cells). With that trend, the binding mechanisms between binder and target also complexify.
Molecular binding assays like tetramer binding and surface plasmon resonance (SPR) measure preconditions for binding, providing limited insights into actual cell binding. Focusing on isolated ligand-receptor interactions or abundance on a molecular level, they can miss the cellular context and often do not correlate well with functional outcomes.
Overcome these challenges with Cell Avidity:
- Generate direct, physiologically relevant measurements of binding in its full, dynamic complexity
- Understand the mechanism of action of your therapeutic products by revealing its complex binding dynamics
- Balance potency and safety by optimizing binding
Cell Avidity tackles on-target off-tumor toxicity in novel CAR-T therapy
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.
Researchers from the Dana-Farber Cancer Institute at Harvard Medical School have developed a cell avidity-based pre-clinical analysis pipeline for CAR selection. This innovative pipeline integrates both safety and potency assessments, utilizing the innovative LUMICKS’ Cell Avidity assays to evaluate a panel of CAR candidates for ccRCC. The Harvard-based team demonstrated a significant improvement with their newly developed G9 anti-CAIX CAR product, which offers potential advance in treatment options for kidney cancer patients.
“Carbonic anhydrase IX (CAIX) was considered undruggable as it is expressed in both tumor and healthy tissues. Fine-tuning the cell avidity of the anti-CAIX chimeric antigen receptor (CAR) T cells ensures CAR-T only kills CAIX high tumor cells but not CAIX low cholangiocytes, thus mitigating the on-target off-tumor side effects.”
Summary of the results. Whereas the G250 anti-CAIX clinical CAR showed off-tumor on-target binding to healthy cells, G9 CARs retains high avidity against high-density CAIX on tumor cells and, crucially, low avidity against low-density CAIX healthy cells (cholangiocytes), indicative of improved safety.
Case study
Cell avidity analysis demonstrates low and safe binding to healthy cells for candidate G9 equivalent to irrelevant negative control CAR-Ts, while showing high avidity for solid tumors similar to G250. This suggested a favorable therapeutic profile for G9, minimizing OTOT effects while maintaining high efficacy.
Dive into the publication
Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects
Wang, Y. et al.
January 1, 2024
https://link.springer.com/article/10.1186/s12943-024-01952-w
Publication
Explore further
Cell Avidity tackles on-target offtumor toxicity in novel CAR-T therapy
App Notes
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.
When Cell Avidity insights would have prevented clinical trial failure: the APRIL-CAR retrospective
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.
Case study
Current short-term in vitro preclinical assays [1] fail to predict the poor APRIL-CAR performance in clinic; poor molecular binding was overlooked, and cellular binding was not assessed before continuation into clinical trials. Incorporating Cell Avidity analysis into the preclinical characterization of CAR T efficacy and safety, can improve the decision-making process and identify better candidates more robustly.
The retrospective study, utilizing conventional in vitro assays such as cytokine secretion and cytotoxicity, revealed robust performance of the APRIL CAR-expressing cells, comparable to two analogous BCMA CARs approved by the FDA (bb2121 and LCAR) (Figure 1).
“In this unique exploration of the reasons underpinning suboptimal clinical responses in the AUTO2 trial, the LUMICKS platform allowed us to establish poor tumor binding (or avidity) by cell bound APRIL compared to competitor CARs as a likely explanation. Only with such studies will the field acquire a greater understanding of the key preclinical readouts that can predict efficacy in patients.”
Figure 2 In the cell-cell context, APRIL CAR insignificant binding to BCMA-expressing target cells, ranking the lower than both FDA-approved clinical CARs (bb2121 and LCAR). Avidity shows % bound CAR T cells from 4 healthy donors against myeloma cell line H929, after 1000 pN force application. Multiple paired T tests and Holm Sidak correction *p<0.05, **p<0.01, ***p<0.001.
Figure 1 Functional assessment of APRIL CAR in vitro does not indicate the mechanism behind the poor efficacy in a Phase-I clinical trial. IFNγ and IL2 release as assessed by ELISA of culture supernatant at 24 hours (left) and Target cell kill as a percentage of targets in media, comparing APRIL to two other BCMA CARs (bb2121 and LCAR (right).
Dive into the publication
Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy
Lee, L. et al.
January 1, 2023
https://jitc.bmj.com/content/11/6/e006699
Publication
Explore further
When Cell Avidity insights would have prevented clinical trial failure: the APRIL-CAR retrospective
App Notes
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.
Solutions
Avidion
The next generation Cell Avidity platform
Ideal for cell therapy candidate screening and large characterization studies. Run up to 4 disposable 48-well cartridges a day for a total of 192 measurements with <80 min. hands-on time.
Avidigo
White glove Cell Avidity services
Full-service contract research from experimental design to data report based on Cell Avidity measurements at high throughput.
z-Movi
For small sized Cell Avidity studies
A fast and simple solution for single-sample Cell Avidity experiments. Run up to 20 measurements per day.
Technical note:
These cards are NOT components because they use the finsweet nested collection logic. To pull in the posible multiple people wo worked on it.
This type of 1-many relation is not supported native in Webflow.
Also this section is hidden when emtpy. To keep everything visible here, that is being done outside the webflow designer from within Slater.
These cards are NOT components because they use the finsweet nested collection logic. To pull in the posible multiple people wo worked on it.
This type of 1-many relation is not supported native in Webflow.
Also this section is hidden when emtpy. To keep everything visible here, that is being done outside the webflow designer from within Slater.
Text Link
Rational Chemical and Genetic Modifications Enhance Avidity and Function of CD70-Directed CAR T Cells for Myeloid Leukemia
Leick, M. B. et al.
2022
Cancer Cell
https://doi.org/10.1016/j.ccell.2022.04.001
Publication
SITC 2025
Conference
April 22, 2025
01-01-20
CAR-TCR Summit 2025
Conference
April 22, 2025
01-01-20
CICON 2025
Conference
April 22, 2025
01-01-20
See more. Know more.
We empower the academic and pharmaceutical communities with cutting-edge technologies to deeply understand the mechanisms of life and disease, driving the discovery and development of life-saving therapies
All products and technologies are for Research Use Only (RUO) except when specifically noted