Abstract
As increasing numbers of broadly neutralizing monoclonal antibodies (mAbs) against HIV-1 enter clinical trials, it is becoming evident that combinations of mAbs are necessary to block infection by the diverse array of globally circulating HIV-1 strains and to limit the emergence of resistant viruses. Multi-specific antibodies, in which two or more HIV-1 entry-targeting moieties are engineered into a single molecule, have expanded rapidly in recent years and offer an attractive solution that can improve neutralization breadth and erect a higher barrier against viral resistance. In some unique cases, multi-specific HIV-1 antibodies have demonstrated vastly improved antiviral potency due to increased avidity or enhanced spatiotemporal functional activity. This review will describe the recent advancements in the HIV-1 field in engineering monoclonal, bispecific and trispecific antibodies with enhanced breadth and potency against HIV-1. A case study will also be presented as an example of the developmental challenges these multi-specific antibodies may face on their path to the clinic. The tremendous potential of multi-specific antibodies against the HIV-1 epidemic is readily evident. Creativity in their discovery and engineering, and acumen during their development, will be the true determinant of their success in reducing HIV-1 infection and disease.
Highlights
The past decade has introduced a new generation of potent and broad neutralizing monoclonal antibodies against human immunodeficiency virus 1 (HIV-1) [1–10], several of which have entered the clinic recently [11–17]
HIV-1 monoclonal antibody (mAb) directed to more conserved components of the viral entry process, such as ibalizumab, which binds to the CD4 receptor on T-cells [23], and PRO140, which binds to the CCR5 co-receptor [24], broadly neutralize a greater fraction of circulating HIV-1 than Envtargeting mAbs [20, 25]
Known as the Antibody Mediated Prevention (AMP) Studies, the lessons learned from these VRC01 Phase 2b efficacy trials will be of tremendous benefit the field of antibody-mediated HIV-1 prevention
Summary
The past decade has introduced a new generation of potent and broad neutralizing monoclonal antibodies (mAbs) against HIV-1 [1–10], several of which have entered the clinic recently [11–17]. Using scFv domains connected in tandem with flexible linkers, different formats of scFv domains targeting the HIV-1 CD4 binding site, V3, and MPER regions were engineered and characterized for their ability to improve antiviral activity and HIV-1 Env binding avidity (Fig. 1g) From these studies, 10E8v4/PGT121-VRC01 emerged as the most promising trispecific antibody candidate, exhibiting 99.5% breadth, as defined by 50% inhibition, an IC50 geometric mean of 0.069, and an IC80 geometric mean of 0.298 μg/ mL [63]. Case study: quality by design approach to engineer a HIV‐1 bispecific antibody with improved developability properties As discussed earlier, 10E8.2/iMab [25] is a CrossMAb format bispecific antibody in which one antigen binding arm (iMab) targets the human CD4 receptor via the Fab of the humanized mAb ibalizumab [23], and a second antigen binding arm (10E8.2) targets the HIV-1 Env MPER via a variant of the human mAb 10E8 (Fig. 1d) [3]. Additional polishing steps purified 10E8.4/iMab to > 97%, which is well within the range of purity acceptable to advance this novel and potent HIV-1 bispecific antibody into clinical evaluation
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