Chemical immunology: Recent advances in tool development and applications

Abstract

Immunology was one of the first biological fields to embrace chemical approaches. The development of new chemical approaches and techniques has provided immunologists with an impressive arsenal of tools to address challenges once considered insurmountable. This review focuses on advances at the interface of chemistry and immunobiology over the past two decades that have not only opened new avenues in basic immunological research, but also revolutionized drug development for the treatment of cancer and autoimmune diseases. These include chemical approaches to understand and manipulate antigen presentation and the T cell priming process, to facilitate immune cell trafficking and regulate immune cell functions, and therapeutic applications of chemical approaches to disease control and treatment.

Keywords: T cell priming; antibody-drug conjugates; cell trafficking; chemical immunology; click chemistry; glycoimmune checkpoints; immunotherapy; innate immune response; proximity labeling; site-specific conjugation.

Figure 1:. The cancer immunity cycle.

Figure 2.. Intercellular Proximity-based labeling to probe cell-cell interactions

Intercellular proximity-based labeling can be achieved via generation of diffusible, small, reactive species or via direct enzymatic tagging of interacting cells. Examples of the former include PhoTag, BioID, MicroMAP, while direct labeling approaches include LIPSTIC or FucoID. The catalyst or enzyme to initiate the labeling can be incorporated into the bait cell by genetic, enzymatic, or chemical strategies.

Figure 3.. Enhancing T cell priming by improving antigen trafficking to lymph nodes

Antigens can be chemically modified to improve lymph node localization via the incorporation of serum-albumin binding 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-Poly(ethylene glycol) (DSPE-PEG). This approach can be applied to CAR antigens as well, and combined with adjuvant for a synergistic effect. Alternatively, nanoparticles formulated with N-azidoacetylmannosamine (ManNAz) target DC in the lymph node and functionalize them with azide handles that can be reacted with modified antigens for more efficient T cell activation.

Figure 4.. Structures of small molecule drugs that facilitate immune cell trafficking or regulate immune cell functions.

Figure 5.. Representative chemical strategies for the targeting of immunosuppressive TME to potentiate anti-tumor responses

Hypersialylation, a hallmark of tumor cells, can be enzymatically removed via targeting a sialidase to tumor cells or the immune synapse. Anti-inflammatory Tregs with upregulated histone H3K27Me3 can be reprogrammed by EZH2 inhibitors. Suppressive functions of macrophages with upregulated IDO can be reversed by IDO inhibitors.

Figure 6.. Chemically induced dimerization (CID).

CID uses small molecule dimerizers to bind two proteins together. Currently available CID strategies include PROTACs which recruits target protein to be ubiquitinated and degraded through the proteasome, LYTACs which engages cell surface LTRs for cell surface proteins to be internalized and degraded through the lysosome, and ARMs which redirects TAA-specific antibodies towards deleterious cells to enhance their killing through the CDC, ADCC or ADCP process.

Figure 7.. Using bioorthogonal conjugation for the construction of site-specific ADCs.

ADCs are composed of a tumor-targeting antibody conjugated to a linker with a cytotoxic payload. Site-specific conjugation can be achieved by genetic incorporation of a biorthogonal handle that is further modified via chemical or enzymatic reactions.

Figure 8.. Leveraging inhibitory Siglec receptors to suppress unwanted immune responses

Siglec-targeting antigenic liposomes (STALs) engage CD22 and BCR on B cells to attenuate antibody formation against autoantigens. Hybrid nanoparticles encapsulating rapamycin and decorated with high-affinity CD22 ligands and antigen both induce co-localization of CD22 and BCR and are phagocytosed by DC, which in turn promote Treg formation. STALs targeting CD33 on mast cells can also suppress anaphylactic responses against allergens.