Merck PD-1 Paper Published
A new study of PD-1 blockade, conducted by researchers at the pharmaceutical company Merck, was published today in the Journal of Immunology. The paper describes Merck’s efforts to create antibodies with the ability to bind PD-1, which led to the selection of a mouse IgG antibody (named 1B8) for testing in the macaque model. Two macaque experiments were conducted: in the first, two groups of four animals with longstanding (>18 months) SIV infection received a single infusion of 1B8 at a dose of 5mg/kg. One group of animals were given the infusion 19 days prior to initiation of antiretroviral therapy (ART) with Merck’s integrase inhibitor, the second group were administered the antibody 12 days after starting ART. Macaques in the first group displayed a transient increase in viral load after antibody administration, similar to that described in the recent paper from researchers at Emory University. By day 19 when ART was started, viral loads had diverged: two of the macaques had levels above baseline (13.2- and 1.8-fold), two slightly below (0.4- and 0.2-fold, in one case below the 1,000 copy limit of the assay). After ART cessation at day 47, the one macaque with undetectable viral load maintained that level for at least nine days. By the last day of follow-up, however, viral loads in all animals had returned to pre-study baseline levels. One macaque that failed to fully control viral load on ART experienced disease progression at day 56 and subsequently had to be euthanized.
In the second group of macaques that received ART prior to PD-1 blockade, the impact of the integrase inhibitor alone on viral load was somewhat variable (at day 12 after ART initiation, viral load was increasing in one animal). After PD-1 blockade, two macaques showed transient increases in viral load after while the other two showed no change. One macaque maintained an undetectable viral load until near the end of ART administration on day 47. Similar to the group given blockade prior to ART, viral loads returned to pre-study baseline in all animals by day 124. The researchers evaluated the impact of PD-1 blockade on the magnitude and function of SIV-specific T cell responses, but no significant differences were observed. In terms of CD4 T cell counts, PD-1 blockade given prior to ART led to an increase in CD4 counts in 3/4 animals (before ART was started) but these increases were not sustained. In the group of animals receiving ART before blockade, CD4 counts increased but the effects of ART versus blockade cannot be distinguished.
The second macaque experiment described in the paper involved vaccination of uninfected animals with a suboptimal dose of an Ad5 vector encoding the SIV Gag protein. Results showed that PD-1 blockade administered at the time of the first immunization significantly increased the Gag-specific CD8 T cell response compared to controls that received the vaccine alone.
Overall, these results compliment but also differ from those obtained recently by researchers at Emory. The viral load reductions documented in the Emory paper were greater overall (2- to 10-fold) and were associated with significant increases in the magnitude and function of SIV-specific T cell and B cell responses, whereas increases in SIV-specific immune responses were not observed in this Merck study. One possible explanation for this difference is that the Emory study gave four infusions of PD-1 blockade over 10 days while the Merck experiments used just a single infusion. Other differences between the studies are that the anti-PD-1 antibody employed by Emory was partially humanized, while Merck employed a fully mouse antibody. The Merck researchers note that macaques in their study rapidly generated antibodies against the mouse antibody, as these antibodies (called rhesus anti-mouse IgG Abs or RAMAs) were detectable by ELISA within 10-14 days of blockade administration. The Emory researchers also saw antibodies arise targeting the mouse-derived parts of their PD-1 antibody. Both research groups stress the importance of developing humanized antibodies for future research; in the words of the Merck team: “One would expect enhanced blockade efficiency and immunological benefit through repeated administrations, ideally with a human-Fc chimeric or fully humanized mAb for optimal pharmacokinetics.”
The results obtained by Merck in the setting of vaccination also highlight the fact that – as prior studies have indicated - PD-1 plays a role in T cell activation as well as T cell exhaustion. As yet, this duality is poorly understood and needs elucidation. Although Merck’s development plans are not clear at this time, it is encouraging that a large pharmaceutical company is exploring the potential for T cell-reviving immune-based therapies. The paper’s authors, led by Adam Finnefrock, express hope that their work “will eventually lead to enhanced prophylactic and therapeutic vaccination modes as well as antiviral and antitumor therapies.”
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