Antibody engineering for increased potency, breadth and half-life

Sievers, Stuart A.; Scharf, Louise; West, Anthony P.; Bjorkman, Pamela J.

The presence of autoreactive/polyreactive antibodies has been associated with HIV-1 infection for more than 25 years [72] [73] [74] . Polyreactivity was first characterized in detail for the 4E10 and 2F5 MPER bNAbs [75] . These bNAbs were described as interacting with cardiolipin, a negatively charged mitochondrial phospholipid [75] [76] [77] [78] [79] [80] . Further studies confirmed that binding of 2F5 and 4E10 to HIV-1 Env is enhanced by the presence of the host-derived viral membrane, which would include negatively charged phospholipids [81] . Recent studies have identified human proteins, kynureninase, type 1 inositol trisphosphate receptor and splicing factor 3b subunit 3 as potential self-antigens recognized by 2F5 and 4E10 [82, 83] . Another MPER antibody, 10E8, does not exhibit polyreactivity in standard assays [84] , yet binds tightly to a self-antigen, FAM84A (family with sequence similarity 84, member A) [85 && ]. In a comprehensive study, a majority of more than 200 anti-HIV-1 Env antibodies isolated from HIV-1 infected donors exhibited binding to both self and nonself antigens, with anti-gp41 antibodies showing the most polyreactivity, particularly against lipid antigens [86, 87] . In general, broadly neutralizing anti-HIV-1 antibodies exhibit a higher frequency of polyreactivity than nonneutralizing antibodies [85 && ]. Polyreactivity may not necessarily be a problem for anti-HIV-1 antibodies, especially as it is a common property of donor-derived bNAbs; however, a correlation between increased polyreactivity and an increased rate of antibody clearance in vivo has been observed for IgGs [88] . IgG half-lives are normally extended beyond other serum proteins due to interactions with FcRn, the receptor that protects serum IgG from a default degradative pathway in vascular endothelial cells [89, 90] . However, mutations known to increase the half-life of nonpolyreactive IgGs through enhanced interactions with FcRn, such as the LS mutation [61] that was introduced into VRC01 and VRC07-523 [54 && ,91] , do not generally improve the half-lives of polyreactive IgGs. This is likely because increased FcRn function cannot compensate for IgG loss due to off-target binding, which absorbs polyreactive IgGs and leads to their rapid clearance [88] .