Antibody engineering for increased potency, breadth and half-life

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

HIV-1 effectively evades antibody-mediated responses due to rapid mutation of gp120 and gp41, the two glycoproteins that comprise the envelope (Env) spike ( Fig. 1 ], and structural features that enable Env to hide conserved epitopes, including a shield of host-derived carbohydrates [5] , conformational masking [6] , steric occlusion [7] [8] [9] [10] and flexible variable loops [8, 11] . The low number and density of envelope spikes on HIV-1 virions may also contribute to the ability of HIV-1 to evade antibodies by preventing most IgGs from binding simultaneously with both Fabs [12,13 & ]. These features usually result in production of strain-specific antibodies. However, recent advances in single-cell cloning techniques have led to the identification of extremely potent, broadly neutralizing HIV-1 IgG antibodies (bNAbs) from infected donors [14] [15] [16] . When delivered passively in animal models of HIV-1 infection, anti-HIV-1 bNAbs can prevent [17] [18] [19] [20] or suppress infection [21] [22] [23] [24] , prompting efforts to improve their potency and/or breadth in order to increase their efficacy as therapeutics. Characterization of bNAbs through structural and bioinformatic approaches has identified epitopes on HIV-1 Env, including the gp120 V1V2 and V3 loops, the CD4-binding site (CD4bs), the gp41 membrane proximal external region (MPER) and sites bridging gp120 and gp41 ( Fig. 1) [25] [26] [27] [28] [29] [30] .