Fc Engineering Service for Effector Function Stimulation

The antibody Fc domain engages with a small family of Fc receptors expressed on immune system cells and other cells to stimulate the rich diversity of positive and negative cell-mediated effector functions. The emergence of monoclonal antibodies for the treatment of various pathological conditions has provided more insights into the biology of Fc receptors and proposed novel strategies for the development of improved therapies using Fc receptor interactions. Although most therapeutic IgGs approved to date retain the natural IgG Fc domain, the knowledge gained in the past few decades provides opportunities for the Fc design of tailored and more effective immunotherapies that have shown fewer side effects and longer half-life.

Creative Biolabs keeps track of the latest advances made in the design of biologics that modulate or exploit Fc receptor-IgG interactions, and are committed to developing the optimal Fc mutation strategy to support the innovative drugs currently being studied in clinical trials, and fine-tune them to achieve premium effector functions (ADCC, ADCP, and CDC).

Fc functions in stimulating the immune system

IgG Fc receptors (such as FcγRI, FcγRIIa and FcγRIIIa) possess the classic cytoplasmic ITAM (immunoreceptor tyrosine-based activation motif) signal transduction domain, and can stimulate immune effector cell activation and subsequent antibody-dependent cell activation (e.g. mediated cytotoxicity (ADCC) or phagocytosis (ADCP). Except for FcγRI, most FcγRs have low affinity for ligands (> 1 mM). This is of vital importance for the development of Fc engineered antibody therapy. Therefore, the weak Fc binding of several key Fc receptors facilitates the engineering of novel monomeric antibodies to achieve the desired therapeutic effect.

Through the modification of the Fc region, the binding of Fc to FcγRIIa on macrophages and FcγRIIIa on NK cells can be enhanced, and these cells can be recruited more effectively, thereby killing tumor cells. Recently, it has been shown in FcgR humanized mice that the Fc binding of human FcγRIIa not only stimulates macrophage-mediated ADCP, but FcγRIIa is also a necessary condition and sufficient for inducing strong anti-tumor cell immunity mediated by dendritic cells and T cells. Such results raise the exciting prospect of coupling Fc-enhanced cytotoxic tumor-targeting antibodies with more non-selective immunostimulants such as checkpoint blockade.

Fig.1 FcR signaling (e.g., FcγRII).^{1, 2}

By manipulating the recruitment of activated and inhibitory receptors, such as through engineered antibodies, a treatment plan can be tailored to the optimal treatment for a specific indication.

Highlight clinical trials of engineered Fc to stimulate the immune system

Studies have reported that single mutations (S239D or I332E), double mutations (S239D/I332E) and triple mutations (S239D/I332E/A330L) in the Fc region can increase the affinity of Fc for FcγRIIa and FcγRIIIa, and the affinity for FcγRIIIa has increased to 169. Times. After these modifications, CD19 and CD96 antibodies all showed stronger ADCC activity. In addition, a point mutation G236A can selectively recognize FcγRIIa but not FcγRIIb, so it can significantly increase ADCP activity. Mutation of G236A and S239D/I332E can increase ADCC and ADCP activity at the same time.

Fig.2 Fc modification for activating the immune system.

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References

1. Ben Mkaddem, Sanae, Marc Benhamou, and Renato C. Monteiro. "Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools." Frontiers in Immunology 10 (2019): 811.
2. under Open Access License CC BY 4.0, without modification.