To understand the mechanism of varlilumab (i.e. IF5hIgG1), Wasiuk et al. tested various murine isotypes on tumors in human CD27-transgenic mice. The IF5mIgG1 isotype was effective against lymphoma, but the potent agonist activity quickly led to apoptosis of T cells, making it ineffective against solid tumors. The IF5mIgG2a isotype elicited only moderate immune activation, but depleted Tregs, leading to sustained antitumor activity against solid tumors. Varlilumab demonstrated dose-dependent intermediate levels of both agonist and depleting activities in mice.

CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcgammaRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcgammaRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.

Author Info: (1) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (2) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (3) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (4) Celldex

Author Info: (1) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (2) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (3) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (4) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (5) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (6) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (7) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (8) Celldex Therapeutics, Inc., Needham, MA 02494. (9) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (10) Celldex Therapeutics, Inc., Needham, MA 02494. (11) Celldex Therapeutics, Inc., Hampton, NJ 08827; and. (12) Celldex Therapeutics, Inc., Hampton, NJ 08827; and lhe@celldex.com.