Abstract SY09-01: Next-generation anti-CTLA-4 antibodies

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.SY09-01-SY09-01
• Main Authors: Korman, Alan J., Engelhardt, John, Loffredo, John, Valle, Jose, Akter, Rahima, Vuyyuru, Raja, Bezman, Natalie, So, Paula, Graziano, Robert, Tipton, Kimberly, West, James, Irving, Bryan, Selby, Mark
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-SY09-01

The activity of ipilimumab as a single agent and in combination with nivolumab (anti-PD-1) in melanoma, as well as the use of ipilimumab/nivolumab combinations in other malignancies, has confirmed the importance of CTLA-4 blockade in immunotherapy. The antitumor effect of this treatment also results in significant immune-related adverse events that limit dosing and result in patient discontinuation. We have taken two approaches to alter the activity of ipilimumab so as to improve its potency and its safety profile. One approach is to enhance the antibody-dependent cellular cytotoxicity (ADCC) activity of ipilimumab in order to increase the potential for Treg depletion at the tumor site; this would be expected to increase the activity of the antibody. The second approach is to produce a prodrug form of ipilimumab (an anti-CTLA-4 Probody therapeutic) that will have reduced activity systemically, but will become proteolytically cleaved at the tumor site to produce the fully functional antibody; the goal of this approach is to reduce the adverse event profile while retaining the antitumor activity of ipilimumab. It has previously been shown that antitumor activity of anti-CTLA-4 antibodies in mouse models of cancer is dependent on the ability of the antibody to bind activating FcγRs and mediate ADCC against Tregs at the tumor site (1, 2). Although human IgG1 Abs have been shown to be effective mediators of ADCC in patients with hematologic malignancies, it is still unclear whether ipilimumab mediates Treg depletion in solid tumors. Using in vitro ADCC assays, we have found that a nonfucosylated (NF) version of ipilimumab (ipilimumab-NF) has increased activity compared to ipilimumab. Ipilimumab-NF also demonstrates increased IL-2 secretion in peripheral mononuclear cells treated with the superantigen SEB as compared to ipilimumab. Transgenic mice that express human FcγRs in the place of mouse FcγRs were used to investigate the activity of anti-mouse surrogate CTLA-4 antibody engineered with either a human IgG1 or human IgG1-NF Fc region in a mouse tumor model. In these mice, the IgG1-NF version of anti-mouse CTLA-4 was found to significantly increase antitumor activity and Treg depletion at the tumor site compared to the IgG1. These data suggest that the clinical activity of ipilimumab could be enhanced by use of the nonfucosylated version of the Ab. In addition, ipilimumab-NF was tested for its ability to enhance a vaccine response in Mauritian cynomolgus maca