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Structural Basis for Cancer Immunotherapy by the First-In-Class

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Structural Basis for Cancer Immunotherapy by the First-In-Class Structural basis for cancer immunotherapy by the PNAS PLUS first-in-class checkpoint inhibitor ipilimumab Udupi A. Ramagopala,1,2, Weifeng Liua,b,1, Sarah C. Garrett-Thomsona,1, Jeffrey B. Bonannoa, Qingrong Yanb,3, Mohan Srinivasanc, Susan C. Wongc, Alasdair Bellc,4, Shilpa Mankikarc, Vangipuram S. Ranganc, Shrikant Deshpandec, Alan J. Kormanc,5, and Steven C. Almoa,5 aDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461; bDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and cBiologics Discovery California, Bristol–Myers Squibb, Redwood City, CA 94063 Edited by James P. Allison, MD Anderson Cancer Center, University of Texas, Houston, TX, and approved April 6, 2017 (received for review November 1, 2016) Rational modulation of the immune response with biologics repre- expressed on activated T effector cells as a result of ligand binding. sents one of the most promising and active areas for the realization Extrinsic effects of CTLA-4 are the consequence of the ability of of new therapeutic strategies. In particular, the use of function CTLA-4 expressed on Tregs to remove B7 ligands from the surface blocking monoclonal antibodies targeting checkpoint inhibitors such of dendritic cells or antigen presenting cells, resulting in significantly as CTLA-4 and PD-1 have proven to be highly effective for the reduced suppression (16). This regulatory mechanism of trans- systemic activation of the human immune system to treat a wide endocytosis may also be operative in activated T effector cells (17, range of cancers. Ipilimumab is a fully human antibody targeting 18). CTLA-4–B7 interactions also have intrinsic effects on Treg, CTLA-4 that received FDA approval for the treatment of metastatic dampening their proliferation or activation (19). melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic Antibodies to CTLA-4 also operate through multiple mecha- for blockade of CTLA-4 and significantly benefits overall survival of nisms. Recent studies in murine models suggest that antibodies patients with metastatic melanoma. Understanding the chemical and targeting CTLA-4 delete intratumoral Treg cells through an Fcγ physical determinants recognized by these mAbs provides direct receptor (FcγR)-dependent process (20, 21). Although Treg de- insight into the mechanisms of pathway blockade, the organization – pletion does not require ligand blocking, ample evidence indicates of the antigen antibody complexes at the cell surface, and opportu- that inhibition of ligand binding to CTLA-4 is an important factor nities to further engineer affinity and selectivity. Here, we report the INFLAMMATION contributing to the antitumor activity of anti–CTLA-4 antibodies in IMMUNOLOGY AND 3.0 Å resolution X-ray crystal structure of the complex formed by murine models as well as in humans. These data include the ipilimumab with its human CTLA-4 target. This structure reveals that β demonstration in murine models that targeting of the effector T-cell ipilimumab contacts the front -sheet of CTLA-4 and intersects with – the CTLA-4:Β7 recognition surface, indicating that direct steric overlap compartment contributes to the antitumor activity of anti CTLA-4, whereas exclusive targeting of the Treg cell compartment failed between ipilimumab and the B7 ligands is a major mechanistic con- — tributor to ipilimumab function. The crystallographically observed to elicit tumor protection thus highlighting the importance of binding interface was confirmed by a comprehensive cell-based bind- ing assay against a library of CTLA-4 mutants and by direct biochem- Significance ical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to Biologics represent a major class of therapeutics for the treat- the homologous and functionally related CD28. ment of malignancies, autoimmune diseases, and infectious diseases. Ipilimumab is the first-in-class immunotherapeutic for immunotherapy | X-ray crystallography | CTLA-4 | ipilimumab | cancer blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. The X-ray crystal structure ctivation of the immune system to target and eliminate ma- of the ipilimumab:CTLA-4 complex defines the atomic interac- Alignancies is recognized as one of the most promising directions tions responsible for affinity and selectivity and demonstrates forcancertherapy(1–4). Two broad strategies for immunotherapy that the therapeutic action of ipilimumab is due to direct steric may be envisaged: inhibition of negative regulators of immune re- competition with the B7 ligands for binding to CTLA-4. sponsiveness (collectively known as checkpoint blockade) (2, 5–8) Author contributions: U.A.R., W.L., S.C.G.-T., J.B.B., Q.Y., M.S., S.C.W., A.B., S.M., V.S.R., and activation of costimulatory pathways (8). A powerful example is S.D., A.J.K., and S.C.A. designed research; U.A.R., W.L., S.C.G.-T., Q.Y., M.S., S.C.W., A.B., provided by antibodies targeting cytotoxic T lymphocyte-associated S.M., V.S.R., and S.D. performed research; U.A.R., W.L., S.C.G.-T., J.B.B., Q.Y., M.S., S.C.W., antigen 4 (CTLA-4), a T-cell surface molecule, which like the ho- A.B., S.M., V.S.R., and S.D. analyzed data; and U.A.R., W.L., S.C.G.-T., M.S., A.J.K., and S.C.A. mologous CD28 (∼30% sequence identity) binds the B7-1 and B7-2 wrote the paper. ligands (9). While CD28 is constitutively expressed and is required, Conflict of interest statement: S.C.A., S.C.G.-T., U.A.R., W.L., and Q.Y. declare no compet- ing financial interests. A.B. is a former employee of Bristol–Myers & Squibb. A.J.K., M.S., in conjunction with TCR engagement, for T-cell activation, CTLA-4 S.C.W., S.M., V.S.R., and S.D. are employees and stockholders of Bristol–Myers & Squibb. is a negative regulator of T-cell function expressed after T-cell ac- This article is a PNAS Direct Submission. tivation to terminate the response. Ipilimumab, a fully human an- Freely available online through the PNAS open access option. tibody targeting CTLA-4 (marketed as Yervoy), demonstrated Data deposition: The crystallography, atomic coordinates, and structure factors have been improved overall survival in two phase-III clinical trials of metastatic deposited in the Protein Data Bank, www.rcsb.org/pdb/home/home.do (PDB ID code melanoma (10, 11) and received FDA approval for the treatment of 5TRU). metastatic melanoma in 2011. Ipilimumab is the first-in-class im- 1U.A.R., W.L., and S.C.G.-T. contributed equally to this work. munotherapeutic for blockade of CTLA-4 and significantly benefits 2Present address: Biological Sciences Division, Poornaprajna Institute of Scientific Re- overall survival of patients with metastatic melanoma. Notably, search, Bangalore 562110, India. combination therapies involving ipilimumab and other immuno- 3Present address: Janssen Pharmaceuticals Inc., Titusville, NJ 08560. modulators/checkpoint antibodies, such as those targeting PD-1 or 4Present address: F-Star Biotechnology Ltd., Cambridge, CB22 3AT, United Kingdom. – – tremelimumab (anti CTLA-4) and anti PD-L1, can result in en- 5To whom correspondence may be addressed. Email: [email protected] or alan. hanced activity (12–15). [email protected]. Multiple mechanisms have been described for CTLA-4 function. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. These include negative signals from intrinsic effects of CTLA-4 1073/pnas.1617941114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1617941114 PNAS Early Edition | 1of10 Downloaded by guest on September 26, 2021 both modalities for antitumor activity (6). Blockade of CTLA-4 also similarity, both CTLA-4 and CD28 use the stereochemical fea- promotes Treg suppression in vitro (6, 19). tures of a shared proline-rich motif (MYPPPY), present in the Human clinical studies with tremelimumab, which, like ipili- loops joining the F and G β strands, to bind the B7-1 and B7-2 mumab, blocks the interactions of CTLA-4 with its ligands, ligands (9). An essential property of any CTLA-4 therapeutic demonstrate that this antibody also has antitumor activity in ad- antibody is the ability to specifically engage CTLA-4, while dition to inducing adverse events (22). Moreover, long-term sur- exhibiting little or no cross-reactivity with CD28. In the case of vival of melanoma patients treated with either ipilimumab (23) or cancer immunotherapy, recognition of CD28 and inhibition of tremelimumab have been reported (24). Notably, tremelimumab ligand binding could inhibit T-cell activation, which would op- harbors the IgG2 isotype and thus cannot engage FcγRs, sup- pose the desired therapeutic activity. To define the nature of the porting a mechanism of action that relies largely on competitive inhibitory mechanism and the specificity exhibited by ipilimumab inhibition with the B7 ligands (ref. 20 and references therein). In for CTLA-4, we report the crystal structure of the complex contrast, ipilimumab is an IgG1 that can engage human FcγR; formed by a Fab fragment of ipilimumab and human CTLA-4, as consistent with this behavior, ipilimumab was shown to mediate well as complementary biochemical studies that confirm the antibody-dependent cell-mediated cytotoxicity (ADCC)-facilitated epitope recognized by ipilimumab. This work unambiguously depletion of Treg cells in vitro (25). However, only small numbers defines the ipilimumab recognition surface on CTLA-4, which of patients have been analyzed for depletion of Treg at the tumor partly overlaps the B7 ligand binding surfaces, indicating that site by ipilimumab (26, 27). Of note, FcγR polymorphisms have no direct steric competition contributes to the function of ipilimu- impact on the survival of ipilimumab-treated patients (28). Im- mab. This work also highlights the determinants responsible for portantly, all aspects of ipilimumab-mediated CTLA-4 blockade the highly selective binding to CTLA-4 and provides the foun- require specific and high-affinity recognition of CTLA-4.
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