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. 2020 Jan-Dec;12(1):1845908.
doi: 10.1080/19420862.2020.1845908.

Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice

Yme U van der Velden  1 , Julien Villaudy  1   2 , Esther Siteur-van Rijnstra  3 , Cynthia A van der Linden  1   3 , Monique A Vink  1 , Edith E Schermer  1 , Kees Weijer  3 , Ben Berkhout  1 , Rogier W Sanders  1   4 , Marit J van Gils  1
Affiliations

Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice

Yme U van der Velden et al. MAbs. 2020 Jan-Dec.

Abstract

Recent studies have shown the potential of broadly neutralizing antibodies (bnAbs) for HIV-1 treatment. One of the candidate antibodies moving into clinical trials is the bnAb PGDM1400. Here, we studied the therapeutic potency and escape pathways of bnAb PGDM1400 during monovalent therapy in human immune system (HIS) mice using the BG505, REJO, MJ4 and AMC008 virus isolates. PGDM1400 administered during chronic infection caused a modest decrease in viral load in the first week of administration in 7 out of 10 animals, which correlated with the in vitro neutralization sensitivity of the viruses to PGDM1400. As expected for monotherapy, viral loads rebounded after about a week and different viral escape pathways were observed, involving the deletion of glycans in the envelope glycoprotein at positions 130 or 160. (Pre)clinical trials should reveal whether PGDM1400 is a useful component of an antibody combination treatment or as part of a tri-specific antibody.

Keywords: HIV-1; PGDM1400; broadly neutralizing antibody; human immune system mouse; therapeutic; viral escape.

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Conflict of interest statement

J.V. was employed by the company AIMM Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. M.J.G and R.W.S are listed on a patent application on PGDM1400.

Figures

Figure 1.
Figure 1.
Therapeutic efficacy of bnAb PGDM1400 in HIS mice. (a) Neutralization sensitivity of BG505, REJO, MJ4 and AMC008 virus to bnAb PGDM1400 in vitro. IC50 and IC90 are indicated by the dotted lines and shown in the table in μg/ml. (b) Viral loads (RNA copies/ml) over time in the HIS mice infected with one of the four viruses. Each line represents one mouse and symbols reflect viral load measurements. The 4 weeks of PGDM1400 administration (20 mg/kg every 7 days) are shaded in gray and arrows for each infection of PGDM1400. (c) The PGDM1400 serum concentration (μg/ml) in each animal in gray with symbols reflecting measurements and the average per group indicated in color. (d) Changes in log10 viral load from start of antibody administration are indicated with each line representing one mouse and the average per group indicated in color
Figure 2.
Figure 2.
Viral escape over time during PGDM1400 treatment. (a) Amino acid sequences of the HIV-1 envelope glycoprotein (amino acid 75–250) obtained from serum RNA per mouse per time point before and during PGDM1400 treatment. The original virus sequence is indicated above those found in the mice infected with that particular virus. The colors are similar to the colors used in Figure 1 as indicated in Figure 1A. The HXB2 sequence on which numbering is based, is included as reference. Known contact residues for PGDM1400 are indicated with *. The glycosylation site at position 130 is shaded in green and the one at position 160 in orange. Identical amino acids are indicated by – and gaps by ~. (b) Neutralization sensitivity of AMC008 virus and AMC008 N130D virus to bnAb PGDM1400. IC50 and IC90 are indicated by the dotted lines
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