ADCC in Immunotherapy

Role of ADCC in Immunotherapy

Targeted therapy with monoclonal antibodies identifies immunotherapy as a novel approach to fighting cancer. The indirect mechanism of therapeutic antibody-induced cell death is related to the host's immune system, which involves complement-mediated cytotoxicity, antibody-dependent cell phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Based on multiple studies, ADCC has been established as an immune mechanism. Trastuzumab is a monoclonal antibody (mAb) against the HER2 receptor in breast cancer that induces cell death by directly inhibiting HER2 signaling and may also activate the immune system to induce an anti-tumor immune response.

Fig.1 Schematic diagram of ADCC

Trastuzumab-mediated ADCC

The Mechanism of ADCC has been validated in clinical patients and is now known to be one of the main mechanisms of rituximab (anti-CD20), cetuximab (anti-EGFR), and trastuzumab. Trastuzumab treatment promotes NK cell activation in BC patients who overexpress Her2, suggesting that the efficacy of trastuzumab is related to the ADCC mechanism.

Given that activation of Her2 signaling requires receptor homodimerization or heterodimerization with other members of the Her2 receptor family, the anti-Her2 antibody pertuzumab was developed to prevent ligand-induced Her2 dimerization. The combined application of pertuzumab and trastuzumab expressed synergistic induction of tumor regression in the BC xenograft model of Her2+. In vitro reviews of trastuzumab and pertuzumab have shown that both of them effectively activate ADCCs with the same potency when used as a single agent. However, in vivo studies, the combined use of trastuzumab and pertuzumab increased NK cell migration to tumors and reduced trastuzumab resistance. Therefore, their combination has a potentiating effect on ADCC compared to their respective monotherapy.

If you are interested in trastuzumab and pertuzumab products, you can find them in our ADCC-Enhanced Biobetters unit!

Strategies and Clinical Progress to Enhance Anti-Her2 ADCC

It is known that the activity of NK cells is determined by the balance of signals produced by inhibitory and activating receptors on the cell surface. Different strategies to enhance NK cell activation can be combined to enhance their ADCC effect.

Fig.2 Different therapeutic approaches targeting HER2+ tumor cells

• Block NK cell inhibitory signals

Monalizumab is an immune checkpoint inhibitor that targets NKG2A receptors expressed on NK cells and tumor-infiltrating cytotoxic CD8+ T cells. Monalizumab blocks the interaction between NKG2A and HLA-E, resuming these cell-mediated anti-tumor responses. It therefore enhances the cytotoxic potential of other therapeutic antibodies.

• Target NK cell activation

Utomilumab is a fully humanized IgG2 monoclonal antibody that is an agonist antibody to 4-1BB. A phase I clinical trial of Utomilumab in combination with trastuzumab or trastuzumab emtansine in patients with HER2-positive BC is ongoing. IL-2 is an immunostimulating cytokine that enhances NK cell responses. IFN-γ is the most efficient mediator of IL-12 action in NK and T cells, stimulating the maturation and cytotoxicity of activated NK cells, CD8+ and CD4+ T cells, as well as enhancing ADCC in anti-tumor cells.

• Combine immune checkpoint inhibitors

Avelumab is an all-human IgG1 anti-PD-L1 monoclonal antibody that retains its Fc partial ability to induce ADCC by binding to CD16. The JAVELINI phase clinical trial for solid tumors used Avelumab as a single agent in patients with metastatic BC who were heavily pretreated and had a lower ORR of 3.0%. However, the response was higher in patients with high PD-L1 expression and persisted for a long time in patients with TNBC subsets. Magrolimab is a humanized monoclonal antibody that blocks CD47's interaction with the signal regulatory protein-α (SIRPα), thereby promoting macrophage-mediated phagocytosis.

• FcγR affinity change

Margetuximab binds to the same HER2 epitope as trastuzumab with equal affinity. It exhibits similar antiproliferative activity to trastuzumab in vitro. Five amino acids were modified into the Margetuximab IgG1 Fc domain by using an engineering platform. These changes increase its binding to the FcγRIIIa activation subtype and reduce its interaction with the inhibitory FcγRIIb.

• Bispecific antibody

Bispecific antibodies (BsAbs) are engineered monoclonal antibodies that contain two binding arms in a single molecule against two different antigens.

Creative Biolabs offers a range of Fc engineering, ADCC enhancement technology, and ADCC antibody production services to help you achieve research and development in the field of tumor immunity. If you are interested, contact us now and the professionals at Creative Biolabs are on hand to answer your questions.

References

1. Zahavi, D.; et al. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib Ther. 2018, 1(1): 7-12.
2. Mandó, P.; et al. Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era. Breast. 2021, 60: 15-25.