AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy
© Wu et al. 2015
Received: 4 July 2015
Accepted: 16 July 2015
Published: 1 August 2015
Monoclonal antibodies against CD20 molecule have been leading the revolution of lymphoma treatment. In addition to monoclonal antibodies against CD20 and CD30, novel agents of immunotherapeutics in clinical development are being developed and are rapidly migrating to clinical application. One area of active development is NK cell activators, such as AFM13. This review will highlight the latest development of AFM13 as the first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy.
Precision therapy with targeted agents against tyrosine kinases and cancer-associated molecules has been leading the revolution of cancer treatment [1–7]. Cancer immunotherapy represents another wave of revolution in cancer therapy [8–13]. In addition to monoclonal antibodies against CD20 and CD30 [14, 15], the main agents of immunotherapeutics in clinical development include the following : (1) immunomodulators (e.g., lenalidomide) ; (2) immune checkpoint blockers (e.g., pembrolizumab, nivolumab, ipilumumab) [10, 11, 17]; (3) T cell activators (e.g., CAR-T19; blinatumomab, AFM11) [18–20]; (4) inhibitors of B cell receptor signaling (e.g., ibrutinib) [2, 21]; and (5) NK cell activators (e.g., AFM13) . AFM13 is a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy.
NK cell-activating bispecific antibody (bsAb)
CD16 (FcγRIII) is a low-affinity receptor for the IgG Fc domain and has two isoforms, CD16A and CD16B . CD16A is an activating receptor mainly expressed on NK cells and macrophages. CD16B is expressed mainly on granulocytes and is not involved in tumor cell killing . CD30 is expressed mainly by the Hodgkin and Reed-Sternberg cells in patients with Hodgkin’s lymphoma (HL). A bispecific antibody against CD30/CD16, HRS-3/A9, was reported to bind to the CD30 antigen with one arm, whereas the other arm binds to the CD16 antigen . This HRS-3/A9 bsAb was shown to recruit and activate NK cells and induce complete remission of CD30+ tumors . Phase I/II studies were done in 15 patients with refractory HL [25, 26]. HRS-3/A9 was infused every 3 to 4 days for a total of 4 times, starting with 1 mg/m2. The maximum tolerated dose (MTD) was not reached at 64 mg/m2, the highest dose administered, because of the limited availability of HRS-3/A9. Nine of the 15 patients developed human anti-mouse Ig antibodies. Four of the patients had an allergic reaction on retreatment. One complete remission (CR) and one partial remission (PR) were seen. These studies led to the further development of NK-activating bsAbs.
AFM13 was studied by the groups in Germany and in MD Anderson Cancer Center in a phase I dose-escalation study in 28 patients who have been heavily pretreated for their relapsed/refractory CD30+ HL (AFM13-101, NCT01221571) . AFM13 was infused weekly for 4 weeks as one cycle at doses ranged between 0.01 and 7 mg/kg body weight. The MTD was not reached. The only dose-limiting toxicity reported in the study was hemolytic anemia in a patient who received 3 infusions at 0.5 mg/kg. Significant NK cell activation and reduction of soluble CD30 in peripheral blood were reported, though the best clinical response was only PR (11.5 %, 3/26 evaluable patients). In patients who received AFM13 at a dose of ≥1.5 mg/kg, the overall response rate was 23 % and the overall disease control rate was 77 % in the heavily pretreated subjects. Brentuximab vedotin (BV) is an antibody-drug conjugate which also binds to CD30 and delivers a chemotherapeutic agent to the CD30+ cells . In this study, AFM13 was found to be active in BV-refractory patients. Since the effector mechanism of these two antibodies is entirely different, AFM13 represents a novel agent for HL refractory to BV.
Issues and future directions
AFM13 is a chimeric antibody with a murine anti-CD30 domain. Antidrug antibodies (ADA) were detected in 15 out of 28 patients. Half of the detected ADAs had neutralizing potential. This remains an issue for further investigation in a large cohort. The half-life of AFM13 was 19 h, which is longer than that of the smaller bispecific BiTE antibody, blinatumomab, which is administered as a continuous infusion [19, 29]. Dosage, dosing-schedules, such as twice-weekly dosing, and duration of treatment are the issues for further investigations. Future studies are also needed for correlation of clinical activity with biomarkers, such as NK cell numbers, and soluble CD30 molecules. Evaluation of these biomarkers in the biopsy specimens will also be informative. A phase II study is underway for this novel tetravalent bsAb AFM13 as the first-in-class NK cell-specific agent for cellular immunotherapy targeting CD30+ malignancies (GHSG-AFM13, NCT02321592). Additional tetravalent bsAbs are also being engineered for targeting other malignancies [20, 30].
Jiaping Fu received a fellowship grant from Shaoxing People’s Hospital, Zhejiang Province, China. Jingjing Wu is a recipient of the Henan Provincial Grant for Overseas Research for Young Leaders of Medical Technology (No. 2014041). The grants supported their research training at the Division of Hematology and Oncology, New York Medical College, USA.
- Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol. 2013;6(1):88.PubMed CentralPubMedView ArticleGoogle Scholar
- Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013;6(1):59.PubMed CentralPubMedView ArticleGoogle Scholar
- Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6(1):27.PubMed CentralPubMedView ArticleGoogle Scholar
- Furqan M, Akinleye A, Mukhi N, Mittal V, Chen Y, Liu D. STAT inhibitors for cancer therapy. J Hematol Oncol. 2013;6(1):90.PubMed CentralPubMedView ArticleGoogle Scholar
- Furqan M, Mukhi N, Lee B, Liu D. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomarker Res. 2013;1(1):5.View ArticleGoogle Scholar
- Huang T, Karsy M, Zhuge J, Zhong M, Liu D. B-Raf and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6(1):30.PubMed CentralPubMedView ArticleGoogle Scholar
- Saha M, Qiu L, Chang H. Targeting p53 by small molecules in hematological malignancies. J Hematol Oncol. 2013;6(1):23.PubMed CentralPubMedView ArticleGoogle Scholar
- Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.PubMed CentralPubMedView ArticleGoogle Scholar
- Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. The New Eng J Med. 2015;373(2):123–35.PubMedView ArticleGoogle Scholar
- Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.PubMedView ArticleGoogle Scholar
- Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.PubMedView ArticleGoogle Scholar
- Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.PubMedView ArticleGoogle Scholar
- Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6(1):74.PubMed CentralPubMedView ArticleGoogle Scholar
- Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10.PubMedView ArticleGoogle Scholar
- Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812–21.PubMedView ArticleGoogle Scholar
- Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759–69.PubMedView ArticleGoogle Scholar
- Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82.PubMedView ArticleGoogle Scholar
- Han E, Li X-l, Wang C-R, Li T-F, Han S-Y. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. J Hematol Oncol. 2013;6(1):47.PubMed CentralPubMedView ArticleGoogle Scholar
- Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.PubMedView ArticleGoogle Scholar
- Reusch U, Duell J, Ellwanger K, Herbrecht C, Knackmuss SH, Fucek I, et al. A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells. MAbs. 2015;7(3):584–604.PubMedView ArticleGoogle Scholar
- Novero A, Ravella P, Chen Y, Dous G, Liu D. Ibrutinib for B cell malignancies. Exp Hematol Oncol. 2014;3(1):4.PubMed CentralPubMedView ArticleGoogle Scholar
- Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(26):4024–31.PubMedView ArticleGoogle Scholar
- Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL. Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc Natl Acad Sci U S A. 1999;96(10):5640–4.PubMed CentralPubMedView ArticleGoogle Scholar
- Hombach A, Jung W, Pohl C, Renner C, Sahin U, Schmits R, et al. A CD16/CD30 bispecific monoclonal antibody induces lysis of Hodgkin’s cells by unstimulated natural killer cells in vitro and in vivo. Int J Cancer. 1993;55(5):830–6.PubMedView ArticleGoogle Scholar
- Hartmann F, Renner C, Jung W, da Costa L, Tembrink S, Held G, et al. Anti-CD16/CD30 bispecific antibody treatment for Hodgkin’s disease: role of infusion schedule and costimulation with cytokines. Clinical Cancer Res. 2001;7(7):1873–81.Google Scholar
- Hartmann F, Renner C, Jung W, Deisting C, Juwana M, Eichentopf B, et al. Treatment of refractory Hodgkin’s disease with an anti-CD16/CD30 bispecific antibody. Blood. 1997;89(6):2042–7.PubMedGoogle Scholar
- Reusch U, Burkhardt C, Fucek I, Le Gall F, Le Gall M, Hoffmann K, et al. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. MAbs. 2014;6(3):728–39.PubMedView ArticleGoogle Scholar
- Holliger P, Prospero T, Winter G. “Diabodies”: small bivalent and bispecific antibody fragments. Proc Natl Acad Sci U S A. 1993;90(14):6444–8.PubMed CentralPubMedView ArticleGoogle Scholar
- Wu J, J Fu, M Zhang, Liu D: Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol 2015, 8:in press.
- Asano R, Shimomura I, Konno S, Ito A, Masakari Y, Orimo R, et al. Rearranging the domain order of a diabody-based IgG-like bispecific antibody enhances its antitumor activity and improves its degradation resistance and pharmacokinetics. MAbs. 2014;6(5):1243–54.PubMedView ArticleGoogle Scholar
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