Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti-CTLA-4 antibody

Abstract

CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen-presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcγ receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent.

Anti–CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control

“…S3). In agreement with this, NK cells have been shown to be able to mediate ADCC of CTLA-4 þ Tregs in the presence of a human CTLA-4 antibody (23). Alternatively, intratumoral Tregs may inhibit NK cells, and anti-CTLA-4-mediated depletion of intratumoral Tregs may indirectly allow for NK-cell activation and degranulation when these NK cells target tumor cells.…”

Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

“…However, the contribution of FcγR interactions to treatment efficacy for CTLA-4 antibodies ipilumumab (hIgG1) and tremelimumab (hIgG2) in patients remains controversial. Our own recent pharmacologic assessment of two CTLA-4 antibodies with identical Fab variable regions and distinct Fc regions (hIgG1 versus hIgG2) revealed an unexpected 40-fold difference in the potency of the hIgG1 variant in a T effector cell assay (Gombos et al, 2018). Notably, this result was not attributed to potential differences in ADCC/P activity between these two Fc variants, but rather supported a yet undefined contribution of the Fc region.…”

“…For instance, emerging evidence suggests that CTLA-4 promotes T cell motility by antagonizing TCR-induced zeta chain-associated protein 70 (ZAP70) microcluster formation, leading to reduced APC-T cell dwell time (Schneider et al, 2008). To date, three anti-CTLA-4 mAbs have demonstrated single-agent anti-tumor activity in patients, although the contribution of FcγR-associated mechanism(s) to the therapeutic activity of these antibodies remains controversial (Arce Vargas et al, 2018; Gombos et al, 2018; Ribas and Flaherty, 2015; Romano et al, 2015). …”

Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells

“…CTLA-4 is also constitutively expressed on T regulatory cells (T reg), which can impair immune response by mediating the removal of B7-1 and B7-2 through trans-endocytosis, thus reducing their stimulatory function [9,10]. In addition, the CTLA-4 cytoplasmatic tail contains a tyrosine motif, which can be phosphorylated, thus creating harbors for SH2 domain of phosphatases and for other intracellular proteins such as the p85 subunit of phosphatidylinositol 3 kinase (PI3K) [11].…”