Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment

Abstract

The majority of monoclonal antibody (mAb) therapeutics possess the ability to engage innate immune effectors through interactions mediated by their fragment crystallizable (Fc) domain. By delivering Fc-Fc gamma receptor (FcγR) and Fc-C1q interactions, mAb are able to link exquisite specificity to powerful cellular and complement-mediated effector functions. Fc interactions can also facilitate enhanced target clustering to evoke potent receptor signaling. These observations have driven decades-long research to delineate the properties within the Fc that elicit these various activities, identifying key amino acid residues and elucidating the important role of glycosylation. They have also fostered a growing interest in Fc-engineering whereby this knowledge is exploited to modulate Fc effector function to suit specific mechanisms of action and therapeutic purposes. In this review, we document the insight that has been generated through the study of the Fc domain; revealing the underpinning structure-function relationships and how the Fc has been engineered to produce an increasing number of antibodies that are appearing in the clinic with augmented abilities to treat cancer.

Nonclinical safety evaluation of pabinafusp alfa, an anti-human transferrin receptor antibody and iduronate-2-sulfatase fusion protein, for the treatment of neuronopathic mucopolysaccharidosis type II

“…CDC, an effector function of IgG (and IgM) antibodies, is a cytolytic cascade triggered by binding of the complement C1q to the constant region of cell-bound antibodies followed by activation of a series of complement proteins [ 19 , 20 ]. Our results showed that, while the anti-hTfR mAb used in pabinafusp alfa elicited CDC, the fusion protein did not.…”

“…ADCC, another effector function of IgG antibodies, is the process of killing opsonized cells (cells coated with antibodies) by effector cells of the immune system, such as natural killer cells [ 19 , 20 ]. Thus, ADCC requires an interaction between the antibody CDR domains and the antigens on target cells as well as binding of the antibody Fc domains to Fcγ receptors on effector cells.…”

“…Our results showed that neither the humanized anti-hTfR mAb nor pabinafusp alfa exerted ADCC under the conditions used in this study. Because the carbohydrate structure of the Fc region is known to be critical for the binding of antibodies to the Fcγ receptors [ 19 , 20 ] and the structure of the anti-TfR mAb moiety in pabinafusp alfa is similar to that of natural IgG1, the binding ability to Fcγ receptors may be retained at least to some degree. In this case, it is possible that the unique binding angle of the mAb to TfR makes it difficult for Fcγ receptors on the effector cells to access the Fc domain of the antibody bound to the target cells, which is an essential step for bridge formation in these cells to initiate ADCC.…”

An Fc-Optimized CD133 Antibody for Induction of NK Cell Reactivity against B Cell Acute Lymphoblastic Leukemia

“…Furthermore, changing the amino acid sequence, exemplified by S239D/I332E (SDIE) in 293C3-SDIE, represents another option. Interestingly, the SDIE-modified CD19 antibody Tafasitamab was recently FDA-approved for the treatment of r/r diffuse large B cell lymphoma (DLBCL), and several other Fc-optimized antibodies carrying the SDIE modification are currently being evaluated in clinical trials [ 35 , 36 ].…”

Optimization of therapeutic antibodies

“…It has been well established that IgG antibodies coating on pathogens can evoke the immune effector functions such as antibody dependent cell-mediated cytotoxicity (ADCC), antibody induced complement dependent cytotoxicity (CDC), and antibody dependent cell-mediated phagocytosis (ADCP) [ 12 , 13 ]. While CDC is mediated and initiated by the binding of Fc domain to the first component of complement, C1q [ 14 ], ADCC and ADCP are executed by the innate immune cells such as natural killer cells and macrophages.…”