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Apoptotic and Antitumor Activity of Death Receptor Antibodies Require Inhibitory Fcγ Receptor Engagement

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Apoptotic and Antitumor Activity of Death Receptor Antibodies Require Inhibitory Fcγ Receptor Engagement Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagement Fubin Li and Jeffrey V. Ravetch1 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021 Contributed by Jeffrey V. Ravetch, May 23, 2012 (sent for review May 9, 2012) By virtue of their ability to induce apoptosis and regulate growth, eradicating established tumors and limiting metastatic disease differentiation, and cytokine responses, the tumor necrosis factor (8–10). However, results from early clinical trials, although prom- receptor (TNFR) superfamily members have emerged as attractive ising, did not match the preclinical activities observed (5, 6, 11–15). targets for anticancer therapeutics. Agonistic antibodies to apoptosis- We reasoned that these differences may result in part from inducing TNFRs, such as death receptor 5 (DR5), although displaying species-specific interactions between the Fc domains of these impressive activities against a variety of tumors in preclinical models, antibodies and their human Fc receptors, which were not appear to be less active in clinical trials. We report that the in vivo addressed in the preclinical studies that led to the development apoptotic and antitumor activities of these antibodies have an of these antibodies. We and others recently reported that ago- absolute requirement for the coengagement of an inhibitory Fcγ nistic anti-CD40 antibodies indeed require specific Fc receptor receptor, FcγRIIB. Anti-DR5 antibodies of the type currently in clinical engagement to activate cytotoxic T cells and thereby target tu- trials have weak FcγRIIB binding and thus are compromised in their proapoptotic and antitumor activities in both colon and breast car- mor cells (16, 17). In contrast to the Fc receptor requirement for cinoma models. Enhancing FcγRIIB engagement increases apoptotic cytotoxic antibodies, such as anti-CD20 and anti-Her2neu, anti- and antitumor potency. Our results demonstrate that Fc domain CD40 antibodies display an absolute requirement for coengage- interactions are critical to the therapeutic activity of anti-DR5 anti- ment of the inhibitory Fcγ receptor FcγRIIB, and consequently, bodies and, together with previous reports on agonistic anti-CD40 its in vivo activity can be enhanced through FcγRIIB-targeted Fc antibodies, establish a common requirement for FcγRIIB coengage- engineering (16–18). ment for optimal biological effects of agonistic anti-TNFR antibodies. The IgG Fc receptors (FcγRs) have emerged as central determinants of the in vivo function of IgG antibodies for such cancer immunotherapy | Fc engineering | human FCGR2B | diverse activities as cytotoxicity, virus and toxin neutralization, antibody-dependent cell-mediated cytotoxicity immunomodulation, and anti-inflammatory responses (19, 20). In both mouse and human, the FcγR system comprises several he tumor necrosis factor receptor (TNFR) superfamily immunoreceptor tyrosine-based activation motif-containing Tmembers are widely expressed on normal and malignant activating FcγRs (FcγRI, FcγRIII, and FcγRIV in mouse; tissues (1, 2) Based on the signaling pathway used by their cy- huFcγRI, huFcγRIIA, and huFcγRIIIA in human) and one toplasmic domains, TNFRs can be broadly divided into those immunoreceptor tyrosine-based inhibitory motif-containing in- receptors that signal through TNFR-associated factors (TRAFs) hibitory FcγR (FcγRIIB in mouse and huFcγRIIB in human). and those known as “death receptors,” which signal through Activating FcγRs are absolutely required for antibody-dependent Fas-associated protein with death domain (FADD) adaptor cell-mediated cytotoxicity (ADCC), which is vital during cancer molecules and result in apoptosis. Signaling transmitted by the immunotherapy (18, 21). The Fc interaction with activating former group regulates many biological processes, including the FcγRs is also critical for IgG antibody-mediated neutralization growth, differentiation, and response to cytokines, in a wide of bacterial toxins and viral pathogens (22–24). In contrast, variety of immune cells. Death receptor-induced apoptosis plays FcγRIIB is a negative regulator of immune cell activation and an important role in the regulation of homeostasis for a variety antibody–antigen immune complex-triggered inflammation, thereby of tissues, including the liver, as well as in the regulation of contributing to the regulation of effector cell activation (25, 26). innate immune cells (3). These pathways are also responsible for In addition, FcγRIIB’s expression on follicular B cells and the intrinsic antitumor response (3, 4), thereby preventing the plasma cells is critical to the maintenance of peripheral tolerance expansion of transformed cells. The central role of TNFRs in – γ regulating both immune responses and apoptosis, along with (27 30). Each Fc R interacts differently with Fcs of the different their expression by many malignant tissues, have made TNFR IgG subclasses within a species and displays unpredictable cross- molecules attractive therapeutic targets for cancer immuno- species interactions, precluding extrapolation from one species therapy (2). Several agonistic anti-TNFR antibodies have been to another. These interactions are critical determinants of the developed for the treatment of solid tumors, including anti-CD40, different biological activities of each IgG subclass. Increased un- a member of the TRAF family of TNFRs, for its ability to activate derstanding of Fc–FcγR interactions has promoted Fc engineering cytotoxic T cells, and anti-DR5, a member of the FADD family that generates Fcs with enhanced or reduced binding affinities to of TNFRs, for its direct apoptotic activity against tumor cells individual FcγRs, thereby optimizing the development of thera- (5, 6). DR5, (also known as TRAIL-R2) and its ligand TRAIL are peutic antibodies (31–33). Here we report on the FcγRrequire- of particular interest, because DR5 is expressed on a variety of ments for agonistic antibodies to apoptosis-inducing members of tumor cells including colon and breast carcinomas, and because the TNFR superfamily, using DR5 as an example. studies in mouse models have shown that DR5 can be targeted to promote strong tumor eradication without damaging normal tis- sues (7, 8). Like other death receptors, after triggering by TRAIL Author contributions: F.L. and J.V.R. designed research; F.L. performed research; F.L. and or agonistic antibodies, DR5 induces apoptosis by recruiting the J.V.R. analyzed data; and F.L. and J.V.R. wrote the paper. FADD adaptor protein, which activates caspase-8 and the down- The authors declare no conflict of interest. stream caspase-3 to execute apoptosis (1). 1To whom correspondence should be addressed. E-mail: [email protected]. Preclinical testing of agonistic anti-TNFR antibodies, including This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. anti-CD40 and anti-DR5, demonstrated significant activity in 1073/pnas.1208698109/-/DCSupplemental. 10966–10971 | PNAS | July 3, 2012 | vol. 109 | no. 27 www.pnas.org/cgi/doi/10.1073/pnas.1208698109 Downloaded by guest on September 26, 2021 − − Results induced hepatotoxicity phenotypes in WT and Fcer1g / mice on − − Impaired Antitumor Effects of MD5-1 in Fcgr2b / Mice. To study both the B6 and BALB/c backgrounds (Figs. S1B and S2). whether FcγRs contribute to the antitumor activities of agonistic – γ anti-DR5 antibodies in vivo, we studied the antitumor activity of MD5-1 Induced Tumor Apoptosis Requires Fc RIIB. Whereas ago- MD5-1, an agonistic Armenian hamster IgG2 anti-mouse DR5 nistic anti-DR5 antibodies may kill tumor cells by mediating antibody (8), in mice carrying FcγR mutations using the MC38 ADCC or triggering DR5 receptor-mediated apoptosis, the colon carcinoma model. As reported previously (10) and shown proapoptotic activity of MD5-1 has been proposed to be re- in Fig. 1A, MD5-1 treatment significantly inhibited the growth of sponsible for both the hepatotoxicity and tumoricidal activity of γ established MC38 tumors in B6 WT mice. This antitumor effect MD5-1 in the MC38 model (10, 34). To test whether Fc RIIB − − – was abolished in B6 mice deficient for FcγRIIB (Fcgr2b / ; Fig. has a direct effect on MD5-1 induced apoptosis, activation of fi – 1B), but was unaffected in B6 mice lacking the FcR common γ caspase-3 was quanti ed in MD5-1 treated MC38 cells cultured −/− fi chain (Fcer1g ; Fig. 1C), which is required for all activating in vitro. By itself, MD5-1 treatment did not induce signi cant FcγRs. These results demonstrate that the antitumor effect of caspase-3 activation in MC38 cells (Fig. 3A); however, in the MD5-1 requires FcγRIIB, but not activating FcγRs. In- presence of WT splenocytes, MD5-1 treatment consistently in- terestingly, although MD5-1 significantly slowed MC38 growth in duced caspase-3 activation in a small but significant fraction of − − Fcer1g / mice, it also caused significant mortality. MC38 cells. This apoptosis-supporting effect of splenotyes depends on their expression of FcγRIIB; neither splenocytes −/− −/− MD5-1–Induced Hepatotoxicity Requires FcγRIIB. We investigated deficient in all FcγRs (Fcer1g Fcgr2b )ordeficient solely in − − − − the accelerated mortality of Fcer1g / mice treated with MD5-1 Fcgr2b / supported MD5-1 to induce apoptosis in MC38 cells. − − to determine the cause of this toxicity. Previous studies demon- In contrast, Fcer1g / splenocytes were superior to WT spleno- strated that MD5-1 induced hepatotoxicity in a strain-dependent
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