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Decoupling Individual Host Response and Immune Cell Engager Cytotoxic Potency
Cristina Gonzàlez Gutierrez1, Adrien Aimard2, Martine Biarnes-Pélicot1
1Aix-Marseille Univ., CNRS, INSERM, LAI, Centuri Living Systems, 13009 Marseille, France.
Abstract:
Immune cell engagers are molecular agents, usually antibody-based constructs, engineered to recruit immune cells against cancer cells and kill them. They are versatile and powerful tools for cancer immunotherapy. Despite the multiplication of engagers tested and accepted in the clinic, how molecular and cellular parameters influence their actions is poorly understood. In particular, disentangling the respective roles of host immune cells and engager biophysical characteristics is needed to improve their design and efficiency. Focusing here on harnessing antibody-dependent Natural Killer cell cytotoxicity, we measure the efficiency of 6 original bispecific antibodies (bsAb), associating an anti-HER2 nanobody and an anti-CD16 nanobody. In vitro cytotoxicity data using primary human NK cells on different target cell lines exposing different antigen densities were collected, exhibiting a wide range of bsAb dose response. In order to rationalize our observations, we introduce a simple multiscale model, postulating that the density of bsAb bridging the two cells is the main parameter triggering the cytotoxic response. We introduce two microscopic parameters: the surface cooperativity describing bsAb affinity at the bridging step and the threshold of bridge density determining the donor-dependent response. Both parameters permit ranking Abs and donors and predicting bsAb potency as a function of antibodies bulk affinities and receptor surface densities on cells. Our approach thus provides a general way to decouple donor response from immune engager characteristics, rationalizing the landscape of molecule design.
Insights
This study introduces a model to understand how bispecific antibodies (bsAbs) engage Natural Killer (NK) cells to kill cancer. The model shows that the density of bsAbs connecting cells is key to triggering cancer cell death.
Area of Science:
- Immunology
- Biotechnology
- Cancer Research
Background:
- Immune cell engagers, often antibody-based, are crucial for cancer immunotherapy.
- Understanding the influence of molecular and cellular factors on engager efficiency is limited.
- Disentangling host immune cell roles and engager biophysical properties is vital for improved design.
Purpose of the Study:
- To investigate the efficiency of bispecific antibodies (bsAbs) in harnessing Natural Killer (NK) cell-mediated cytotoxicity against cancer.
- To develop a model that rationalizes the dose-response of bsAbs based on molecular and cellular parameters.
- To decouple donor-specific responses from immune engager characteristics for optimized design.
Main Methods:
- Evaluated 6 novel bispecific antibodies (bsAbs) combining anti-HER2 and anti-CD16 nanobodies.
- Collected in vitro cytotoxicity data using primary human NK cells against target cell lines with varying HER2 antigen densities.
- Developed a multiscale model linking bsAb density to cytotoxic response.
Main Results:
- Observed a wide range of bsAb dose responses in cytotoxicity assays.
- The model identified bsAb density bridging immune and target cells as the primary trigger for cytotoxicity.
- Introduced 'surface cooperativity' and 'bridge density threshold' parameters to rank antibodies and predict potency.
Conclusions:
- The developed model provides a framework to understand and predict the efficacy of bsAbs in NK cell-mediated cancer immunotherapy.
- The model successfully decouples donor-dependent responses from immune engager properties.
- This approach aids in rationalizing the design of more efficient immune engagers for cancer treatment.
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