Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties
Jeffrey L Nordstrom, Sergey Gorlatov, Wenjun Zhang, Yinhua Yang, Ling Huang, Steve Burke, Hua Li, Valentina Ciccarone, Tengfei Zhang, Jeffrey Stavenhagen, Scott Koenig, Stanford J Stewart, Paul A Moore, Syd Johnson, Ezio Bonvini, Jeffrey L Nordstrom, Sergey Gorlatov, Wenjun Zhang, Yinhua Yang, Ling Huang, Steve Burke, Hua Li, Valentina Ciccarone, Tengfei Zhang, Jeffrey Stavenhagen, Scott Koenig, Stanford J Stewart, Paul A Moore, Syd Johnson, Ezio Bonvini
Abstract
Introduction: Response to trastuzumab in metastatic breast cancer correlates with expression of the high binding variant (158V) of the activating Fcγ receptor IIIA (CD16A). We engineered MGAH22, a chimeric anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab, with an Fc domain engineered for increased binding to both alleles of human CD16A.
Methods: MGAH22 was compared to an identical anti-HER2 mAb except for a wild type Fc domain. Antibody-dependent cell cytotoxicity (ADCC) assays were performed with HER2-expressing cancer cells as targets and human PBMC or purified NK cells as effectors. Xenograft studies were conducted in mice with wild type murine FcγRs; in mice lacking murine CD16; or in mice lacking murine CD16 but transgenic for human CD16A-158F, the low-binding variant. The latter model reproduces the differential binding between wild type and the Fc-optimized mAb for human CD16A. The JIMT-1 human breast tumor line, derived from a patient that progressed on trastuzumab therapy, was used in these studies. Single and repeat dose toxicology studies with MGAH22 administered intravenously at high dose were conducted in cynomolgus monkeys.
Results: The optimized Fc domain confers enhanced ADCC against all HER2-positive tumor cells tested, including cells resistant to trastuzumab's anti-proliferative activity or expressing low HER2 levels. The greatest improvement occurs with effector cells isolated from donors homozygous or heterozygous for CD16A-158F, the low-binding allele. MGAH22 demonstrates increased activity against HER2-expressing tumors in mice transgenic for human CD16A-158F. In single and repeat-dose toxicology studies in cynomolgus monkeys, a species with a HER2 expression pattern comparable to that in humans and Fcγ receptors that exhibit enhanced binding to the optimized Fc domain, MGAH22 was well tolerated at all doses tested (15-150 mg/kg) and exhibited pharmacokinetic parameters similar to that of other anti-HER2 antibodies. Induction of cytokine release by MGAH22 in vivo or in vitro was similar to that induced by the corresponding wild type mAb or trastuzumab.
Conclusions: The data support the clinical development of MGAH22, which may have utility in patients with low HER2 expressing tumors or carrying the CD16A low-binding allele.
Figures
References
- Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. doi: 10.1126/science.3798106.
- Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–2648.
- Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101.
- Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. doi: 10.1056/NEJMoa052122.
- Bang YJ, Van CE, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697. doi: 10.1016/S0140-6736(10)61121-X.
- Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27:5838–5847. doi: 10.1200/JCO.2009.22.1507.
- Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6:443–446. doi: 10.1038/74704.
- Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C, Cabaret V, Fermeaux V, Bertheau P, Garnier J, Jeannin JF, Coudert B. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259–267. doi: 10.1038/sj.bjc.6602930.
- Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, Castiglioni F, Villani L, Magalotti C, Gibelli N, Oliviero B, Ballardini B, Da PG, Zambelli A, Costa A. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10:5650–5655. doi: 10.1158/1078-0432.CCR-04-0225.
- Varchetta S, Gibelli N, Oliviero B, Nardini E, Gennari R, Gatti G, Silva LS, Villani L, Tagliabue E, Menard S, Costa A, Fagnoni FF. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 2007;67:11991–11999. doi: 10.1158/0008-5472.CAN-07-2068.
- Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, Laccabue D, Zerbini A, Camisa R, Bisagni G, Neri TM, Ardizzoni A. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26:1789–1796. doi: 10.1200/JCO.2007.14.8957.
- Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, Iqbal S, Groshen S, Lenz HJ. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007;25:3712–3718. doi: 10.1200/JCO.2006.08.8021.
- Bibeau F, Lopez-Crapez E, Di FF, Thezenas S, Ychou M, Blanchard F, Lamy A, Penault-Llorca F, Frebourg T, Michel P, Sabourin JC, Boissiere-Michot F. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol. 2009;27:1122–1129. doi: 10.1200/JCO.2008.18.0463.
- Pander J, Gelderblom H, Antonini NF, Tol J, van Krieken JH, van der Straaten T, Punt CJ, Guchelaar HJ. Correlation of FCGR3A and EGFR germline polymorphisms with the efficacy of cetuximab in KRAS wild-type metastatic colorectal cancer. Eur J Cancer. 2010;46:1829–1834. doi: 10.1016/j.ejca.2010.03.017.
- Pander J, Heusinkveld M, van der Straaten T, Jordanova ES, Baak-Pablo R, Gelderblom H, Morreau H, van der Burg SH, Guchelaar HJ, van HT. Activation of tumor-promoting type 2 macrophages by EGFR-targeting antibody cetuximab. Clin Cancer Res. 2011;17:5668–5673. doi: 10.1158/1078-0432.CCR-11-0239.
- Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–3947. doi: 10.1200/JCO.2003.05.013.
- Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754–758. doi: 10.1182/blood.V99.3.754.
- Canete JD, Suarez B, Hernandez MV, Sanmarti R, Rego I, Celis R, Moll C, Pinto JA, Blanco FJ, Lozano F. Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1547–1552. doi: 10.1136/ard.2008.096982.
- Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, Li Y, Pitti R, Totpal K, Yee S, Ross S, Vernes JM, Lu Y, Adams C, Offringa R, Kelley B, Hymowitz S, Daniel D, Meng G, Ashkenazi A. An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell. 2011;19:101–113. doi: 10.1016/j.ccr.2010.11.012.
- Sullivan KE, Jawad AF, Piliero LM, Kim N, Luan X, Goldman D, Petri M. Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus. Rheumatology (Oxford) 2003;42:446–452. doi: 10.1093/rheumatology/keg157.
- Kyogoku C, Dijstelbloem HM, Tsuchiya N, Hatta Y, Kato H, Yamaguchi A, Fukazawa T, Jansen MD, Hashimoto H, van De Winkel JG, Kallenberg CG, Tokunaga K. Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to genetic susceptibility. Arthritis Rheum. 2002;46:1242–1254. doi: 10.1002/art.10257.
- Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34–47. doi: 10.1038/nri2206.
- Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA. 1992;89:4285–4289. doi: 10.1073/pnas.89.10.4285.
- Stavenhagen JB, Gorlatov S, Tuaillon N, Rankin CT, Li H, Burke S, Huang L, Johnson S, Koenig S, Bonvini E. Enhancing the potency of therapeutic monoclonal antibodies via Fc optimization. Adv Enzyme Regul. 2008;48:152–164. doi: 10.1016/j.advenzreg.2007.11.011.
- Stavenhagen JB, Gorlatov S, Tuaillon N, Rankin CT, Li H, Burke S, Huang L, Vijh S, Johnson S, Bonvini E, Koenig S. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res. 2007;67:8882–8890. doi: 10.1158/0008-5472.CAN-07-0696.
- Code of Federal Regulations, Title 9, Animals and Animal Products.
- National Research Council, Institute of Laboratory Animal Resources. Guide for the Care and Use of Laboratory Animals. Washington DC: National Academy Press; 1996.
- Tanner M, Kapanen AI, Junttila T, Raheem O, Grenman S, Elo J, Elenius K, Isola J. Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. Mol Cancer Ther. 2004;3:1585–1592.
- Rogers KA, Scinicariello F, Attanasio R. IgG Fc receptor III homologues in nonhuman primate species: genetic characterization and ligand interactions. J Immunol. 2006;177:3848–3856.
- Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23:41–51. doi: 10.1016/j.immuni.2005.05.010.
- Mancardi DA, Iannascoli B, Hoos S, England P, Daeron M, Bruhns P. FcgammaRIV is a mouse IgE receptor that resembles macrophage FcepsilonRI in humans and promotes IgE-induced lung inflammation. J Clin Invest. 2008;118:3738–3750. doi: 10.1172/JCI36452.
- Asada S, Choi Y, Yamada M, Wang SC, Hung MC, Qin J, Uesugi M. External control of Her2 expression and cancer cell growth by targeting a Ras-linked coactivator. Proc Natl Acad Sci USA. 2002;99:12747–12752. doi: 10.1073/pnas.202162199.
- Perussia B, Ravetch JV. Fc gamma RIII (CD16) on human macrophages is a functional product of the Fc gamma RIII-2 gene. Eur J Immunol. 1991;21:425–429. doi: 10.1002/eji.1830210226.
- Shepard HM, Jin P, Slamon DJ, Pirot Z, Maneval DC. Herceptin. Handb Exp Pharmacol. 2008;181:183–219. doi: 10.1007/978-3-540-73259-4_9.
- Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006;55:717–727. doi: 10.1007/s00262-005-0058-x.
- Junttila TT, Parsons K, Olsson C, Lu Y, Xin Y, Theriault J, Crocker L, Pabonan O, Baginski T, Meng G, Totpal K, Kelley RF, Sliwkowski MX. Superior in vivo efficacy of afucosylated trastuzumab in the treatment of HER2-amplified breast cancer. Cancer Res. 2010;70:4481–4489. doi: 10.1158/0008-5472.CAN-09-3704.
- Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, Chan C, Chung HS, Eivazi A, Yoder SC, Vielmetter J, Carmichael DF, Hayes RJ, Dahiyat BI. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA. 2006;103:4005–4010. doi: 10.1073/pnas.0508123103.
- Richards JO, Karki S, Lazar GA, Chen H, Dang W, Desjarlais JR. Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther. 2008;7:2517–2527. doi: 10.1158/1535-7163.MCT-08-0201.
- Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, Nakamura K, Shitara K. Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. Clin Cancer Res. 2005;11:2327–2336. doi: 10.1158/1078-0432.CCR-04-2263.
- Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF. American Society of Clinical Oncology/College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18–43.
- Shields RL, Lai J, Keck R, O'Connell LY, Hong K, Meng YG, Weikert SHA, Presta LG. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem. 2002;277:26733–26740. doi: 10.1074/jbc.M202069200.
- Uchida J, Lee Y, Hasegawa M, Liang Y, Bradney A, Oliver JA, Bowen K, Steeber DA, Haas KM, Poe JC, Tedder TF. Mouse CD20 expression and function. Int Immunol. 2004;16:119–129. doi: 10.1093/intimm/dxh009.
- Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J Clin Invest. 2005;115:2914–2923. doi: 10.1172/JCI24772.
- Desai DD, Harbers SO, Flores M, Colonna L, Downie MP, Bergtold A, Jung S, Clynes R. Fc gamma receptor IIB on dendritic cells enforces peripheral tolerance by inhibiting effector T cell responses. J Immunol. 2007;178:6217–6226.
- Dhodapkar KM, Kaufman JL, Ehlers M, Banerjee DK, Bonvini E, Koenig S, Steinman RM, Ravetch JV, Dhodapkar MV. Selective blockade of inhibitory Fcgamma receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc Natl Acad Sci USA. 2005;102:2910–2915. doi: 10.1073/pnas.0500014102.
- Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu Rev Immunol. 2000;18:739–766. doi: 10.1146/annurev.immunol.18.1.739.
- Shankar G, Pendley C, Stein KE. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol. 2007;25:555–561. doi: 10.1038/nbt1303.
- Cresti N, Jamieson D, Verrill MW, Pinkilgton M, Boddy AV. Fc{gamma}-receptor IIa polymorphism and cardiotoxicity in patients with breast cancer treated with adjuvant trastuzumab. ASCO Meeting Abstracts. 2011;29:565.
- Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RVJ, Lutz RJ, Wong WL, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–9290. doi: 10.1158/0008-5472.CAN-08-1776.
- Burris HA, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O'Shaughnessy JA. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29:398–405. doi: 10.1200/JCO.2010.29.5865.
Source: PubMed