Fc Receptors & Antibody Effector Function
A therapeutic antibody does two jobs, and the second one is decided by its Fc. The variable domains choose the target; the constant region decides what happens next — and that choice is made by which Fcγ receptor the Fc engages. CD64 binds monomeric IgG with high affinity; CD16 and FcγRIV need immune complexes but drive ADCC; CD32B is the one inhibitory receptor in the family and subtracts from everything the others do. All the activating ones signal through the same ITAM-bearing FcεRIγ chain into LYN, SYK, BTK and PLCγ2; CD32B answers with SHIP1 and SHP-1. Downstream the map splits three ways: ADCC through perforin and granzyme B, ADCP through CD11b/CD18 against the CD47–SIRPα brake, and CDC through C1q, C4, C3 and the C5b-9 pore. FcRn sits outside all of it, setting half-life. Click any protein for the matching Assay Genie In Vivo antibody or ELISA kit.
The Fcγ receptor family is an arithmetic problem, not a switch. Four receptors in the mouse and five in the human, all binding the same IgG Fc, differing in affinity, in cell distribution and — crucially — in sign. CD64 (FcγRI) binds monomeric IgG with nanomolar affinity and is therefore occupied at baseline by circulating antibody, which is exactly why it contributes less to therapeutic-antibody activity than its affinity suggests. CD16 (FcγRIII) and FcγRIV are low-affinity and only fire when IgG is multimerised on a target surface — the property that makes them the ADCC receptors. CD32B (FcγRIIB) is the single inhibitory member, and it is expressed on B cells and myeloid cells alongside the activating ones. What a cell does when antibody arrives is the sum of activating and inhibitory engagement, not the action of one receptor.
One ITAM chain, one kinase cascade. The activating receptors have little cytoplasmic tail of their own; they signal through the associated FcεRIγ chain, whose ITAM motifs are phosphorylated by LYN and then dock SYK. From there the cascade runs through BTK and PLCγ2 to calcium, and through VAV1 to RAC1 and the actin rearrangement that phagocytosis requires. CD32B uses an ITIM instead and recruits SHIP1, which hydrolyses PIP3 and starves the BTK/PLCγ2 step, plus SHP-1. Because activation and inhibition converge on the same second messengers, the ratio of receptor engagement is the variable that matters — the reason Fc engineering works at all.
Three effector mechanisms, three different rate-limiting steps. ADCC is NK-dominated, needs CD16 crosslinking, and ends in perforin and granzyme B. ADCP is macrophage-dominated, needs CD11b/CD18 and actin, and is gated by the CD47–SIRPα "don't eat me" axis running against the calreticulin– LRP1 "eat me" signal — which is why an opsonised cell can still resist phagocytosis if CD47 is high. CDC needs hexameric IgG to fix C1q, then runs C4, C3 and C5 to the C5b-9 membrane pore, with C5a/C5aR1 as the inflammatory by-product. An antibody can be excellent at one of these and useless at the others, and measuring only one will tell you the wrong thing about the molecule.
FcRn is the odd one out, and the reason isotype matters for dosing. FcRn is not an activating receptor at all: it binds IgG in acidified endosomes and recycles it back to the surface, rescuing it from lysosomal degradation. That single mechanism sets the ~3-week half-life of IgG and explains both Fc half-life engineering and the mechanism of FcRn-blocking therapies in autoantibody disease. The In Vivo tie-in: functional-grade antibodies against CD16-2 (FcγRIV), CD32/CD16 (clone 2.4G2), CD11b, CD18, CD47 and NK1.1 let you remove one effector arm at a time and attribute activity properly — the standard control set for any depleting-antibody experiment, because an isotype that depletes through Fc is not an inert carrier but part of the mechanism. For research use only; not for use in diagnostic or therapeutic procedures.
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