UCLA researchers in the Department of Bioengineering have developed a platform advancing systems serology that profiles the Fc properties of anti-tumor antibodies (ATAbs) to provide more nuanced understanding of a cancer’s humoral immunity and better guide therapeutic approaches towards overcoming the immune dysregulation.
BACKGROUND:
Antibodies have tumor-eliminating potential: they can block cell surface receptor signaling, prime cancer cells for immune destruction, and block signals that are preventing immune responses. Anti-tumor antibodies (ATAbs) induce abundant active humoral immune response against many tumor types. However, due to mechanisms of cancer immune evasion, ATAbs only weakly induce tumor cell death in vitro and are ineffective at eliminating tumors in vivo. Recently, studies of monoclonal Ab therapies for infectious disease have revealed that regulation of Ab responses occurs not only through antigen binding but also a network of immune receptor interactions via Fc domains of antibodies. The properties of Fc domains, including type, isotype, and glycan changes, play a significant role in determining the nature and magnitude of ATAb immune responses. In infectious disease studies, system serological techniques to profile Ab Fc properties have been applied. These approaches involve enrichment of antibodies with antigen-conjugated beads and detection of Fc properties with florescent reagents. These measurements quantitatively reflect regulatory changes in Fc composition, predict functional immune cell responses, and identify mechanisms of antibody-mediated protection. However, this standard system serology approach is precluded in cancer studies by the complexity and uniqueness of antigen targets in tumor cells. Given that it is critical to determine Fc properties for enhanced understanding of cancer humoral immunity, a standard systematic serological method to determine these properties of ATAbs could revolutionize cancer therapy.
INNOVATION:
UCLA researchers led by Dr. Aaron Meyer in the Department of Bioengineering have developed a novel systems serology platform for profiling the Fc properties of ATAbs. The researchers have implemented an optimized protocol to selectively isolate ATAbs. They have demonstrated successful quantitative profiling of Fc properties using known mixtures of monoclonal Abs. This assay shows high sensitivity and reproducibility in various metrics, including the ability to predict immune effector cell-elicited responses in a panel of high-grade serous ovarian carcinomas. Using the assay, researchers demonstrated that the Fc properties of ATAbs have distinct properties from those against viruses in the same patients, and the differences consistently correlated with poor induction of effector responses. Characterizing ATAb Fc properties as an important regulatory checkpoint indicates new therapeutic approaches for overcoming anti-tumor immune dysregulation.
POTENTIAL APPLICATIONS:
- Reveal the regulatory mechanism by which ATAbs are ineffective at tumor elimination
- Characterize the specific antibody-immune receptor interactions that predict treatment response and other clinical features
- Allow for high-resolution monitoring of tumor immune responses
- Enable the development of a personalized autologous therapy
- Serve as an effective prognostic signal for predicting and monitoring therapeutic responses
ADVANTAGES:
- The assay has been shown to be effectively quantitative, comprehensive, and multiplexed in profiling the immune receptor interactions of ATAbs
- The platform is easily adopted clinically as antibodies are systemic and easily accessible through a blood dra
- This approach could potentially be applied in other diseases where the antigen targets are unknown or complex but the cellular targets are known, such as in autoimmune diseases