The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models

Published on Aug 1, 2019in Haematologica7.116
· DOI :10.3324/HAEMATOL.2018.211011
Stuart W. Hicks15
Estimated H-index: 15
(ImmunoGen, Inc.),
Chiara Tarantelli12
Estimated H-index: 12
(USI: University of Lugano)
+ 15 AuthorsFrancesco Bertoni78
Estimated H-index: 78
(USI: University of Lugano)
Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.
📖 Papers frequently viewed together
137 Citations
4 Authors (John M. Lambert, ..., Anne Bousseau)
1 Citations
#1Pashna N. Munshi (MedStar Georgetown University Hospital)H-Index: 6
#1Pashna N. Munshi (MedStar Georgetown University Hospital)H-Index: 2
Last. Chaitra S. Ujjani (Fred Hutchinson Cancer Research Center)H-Index: 16
view all 2 authors...
: Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies ha...
3 CitationsSource
#1Najat Bouchkouj (CBER: Center for Biologics Evaluation and Research)H-Index: 2
#2Yvette L. Kasamon (CDER: Center for Drug Evaluation and Research)H-Index: 5
Last. Richard Pazdur (FDA: Food and Drug Administration)H-Index: 54
view all 10 authors...
In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients re...
68 CitationsSource
#1Maura C. O'Leary (CBER: Center for Biologics Evaluation and Research)H-Index: 1
#2Xiaobin Lu (CBER: Center for Biologics Evaluation and Research)H-Index: 1
Last. Richard Pazdur (FDA: Food and Drug Administration)H-Index: 54
view all 13 authors...
Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals, East Hanover, NJ) is a CD19-directed genetically-modified autologous T-cell immunotherapy. On August 30, 2017, the U.S. Food and Drug Administration approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR and minimal residual disease (MRD)
66 CitationsSource
#1Emily Y. Jen (CDER: Center for Drug Evaluation and Research)H-Index: 3
#2Qing Xu (CDER: Center for Drug Evaluation and Research)H-Index: 1
Last. Richard Pazdur (FDA: Food and Drug Administration)H-Index: 89
view all 11 authors...
On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP-ALL. The basis for this accelerated approval was a single-arm trial. For the 86 p...
46 CitationsSource
#1E. Dianne Pulte (CDER: Center for Drug Evaluation and Research)H-Index: 3
#2Jonathon Vallejo (CDER: Center for Drug Evaluation and Research)H-Index: 3
Last. Richard Pazdur (CDER: Center for Drug Evaluation and Research)H-Index: 89
view all 8 authors...
: On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-o...
21 CitationsSource
#1Victor A. Chow (Fred Hutchinson Cancer Research Center)H-Index: 5
#2Mazyar Shadman (Fred Hutchinson Cancer Research Center)H-Index: 17
Last. Ajay K. Gopal (Fred Hutchinson Cancer Research Center)H-Index: 51
view all 3 authors...
Chimeric antigen receptor (CAR) T-cells demonstrate efficacy in B-cell malignancies, leading to FDA approval of axicaptagene ciloleucel in October 2017 and tisagenlecleucel in May 2018 for large B-cell lymphomas after two prior lines of therapy. Durable remissions are seen in 30-40% of study-treated patients, but unique toxicities of cytokine release syndrome and neurotoxicity require administration in specialized centers. This article reviews the data to-date within the context of current diffu...
60 CitationsSource
#1Wojciech Jurczak (Jagiellonian University)H-Index: 33
#2Pier Luigi Zinzani (UNIBO: University of Bologna)H-Index: 105
Last. Kristie A. Blum (OSU: Ohio State University)H-Index: 61
view all 14 authors...
Abstract Background This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin’s lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into...
48 CitationsSource
#1G. IacoboniH-Index: 1
#2Emanuele ZuccaH-Index: 83
Last. Anastasios StathisH-Index: 24
view all 4 authors...
Abstract Background The first-line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been carried out over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and methods Reports of phase III trials evaluating the addition ...
9 CitationsSource
#1Yelena Kovtun (ImmunoGen, Inc.)H-Index: 19
#2P. Noordhuis (VUmc: VU University Medical Center)H-Index: 18
Last. Jan Pinkas (ImmunoGen, Inc.)H-Index: 11
view all 14 authors...
The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent has however been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the desi...
30 CitationsSource
#1Anastasios StathisH-Index: 24
#2Alexia Iasonos (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 54
Last. Anas Younes (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 92
view all 7 authors...
The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models...
3 CitationsSource
Cited By10
Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. ...
1 CitationsSource
#1M. Knödler (Fraunhofer Society)H-Index: 1
#2Johannes F. Buyel (Fraunhofer Society)H-Index: 18
Abstract Molecular farming in plants is an emerging platform for the production of pharmaceutical proteins, and host species such as tobacco are now becoming competitive with commercially established production hosts based on bacteria and mammalian cell lines. The range of recombinant therapeutic proteins produced in plants includes replacement enzymes, vaccines and monoclonal antibodies (mAbs). But plants can also be used to manufacture toxins, such as the mistletoe lectin viscumin, providing a...
2 CitationsSource
#1Josefa Chuh (Genentech)H-Index: 11
#2MaryAnn Go (Genentech)H-Index: 5
Last. Nicholas J. Agard (Genentech)H-Index: 1
view all 27 authors...
Early success with brentuximab vedotin in treating classical Hodgkin lymphoma spurred an influx of at least 20 monomethyl auristatin E (MMAE) antibody-drug conjugates (ADCs) into clinical trials. While three MMAE-ADCs have been approved, most of these conjugates are no longer being investigated in clinical trials. Some auristatin conjugates show limited or no efficacy at tolerated doses, but even for drugs driving initial remissions, tumor regrowth and metastasis often rapidly occur. Here we des...
#1Filippo SprianoH-Index: 7
#2Eugenio GaudioH-Index: 27
Last. Francesco BertoniH-Index: 78
view all 19 authors...
Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of actio...
6 CitationsSource
#1Marilia Barreca (University of Palermo)H-Index: 3
#2Anastasios StathisH-Index: 24
Last. Francesco BertoniH-Index: 78
view all 4 authors...
Abstract Anti-tubulin agents constitute a large class of compounds with broad activity both in solid tumors and hematologic malignancies, due to the interference with microtubule dynamics. Since microtubules play crucial roles in the regulation of the mitotic spindles, the interference with their function usually leads to a block in cell division with arrest at the metaphase/anaphase junction of mitosis, followed to apoptosis. This explains the reason why tubulin-binding agents (TBAs) proved to ...
5 CitationsSource
#1Li Wang (SJTU: Shanghai Jiao Tong University)H-Index: 84
#1Li Wang (SJTU: Shanghai Jiao Tong University)H-Index: 1
Last. Wei-Li Zhao (SJTU: Shanghai Jiao Tong University)H-Index: 19
view all 8 authors...
The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors ...
20 CitationsSource
#1Eugenio Gaudio (USI: University of Lugano)H-Index: 10
#2Chiara Tarantelli (USI: University of Lugano)H-Index: 12
Last. Francesco BertoniH-Index: 78
view all 28 authors...
Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leuke...
8 CitationsSource
#1Dalma DeakH-Index: 4
#2Cristina PopH-Index: 1
Last. Ciprian TomuleasaH-Index: 24
view all 27 authors...
Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resi...
5 CitationsSource
#1Qing ZhongH-Index: 1
#2Bing-Hui Li (WHU: Wuhan University)H-Index: 5
Last. Ying-Hui Jin (WHU: Wuhan University)H-Index: 6
view all 6 authors...
Background Childhood leukemia is one of the most common cancers in children. As a potential treatment for leukemia, immunotherapy has become a new research hotspot. This research aimed at exploring the status and trends of current researches on immunotherapy for childhood leukemia through bibliometric analysis. Methods The Institute for Scientific Information (ISI) Web of Science core collection database was searched for articles on immunotherapy and childhood leukemia using computer. Time perio...
2 CitationsSource
#1Filippo Spriano (USI: University of Lugano)H-Index: 7
#2Elaine Yee Lin Chung (USI: University of Lugano)H-Index: 2
Last. Francesco Bertoni (USI: University of Lugano)H-Index: 78
view all 23 authors...
Purpose: Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due to their nonenzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 and its clinical derivative, TK-216, targeting ETS factors via blocking the protein–protein interaction with RNA helicases, for their ant...
15 CitationsSource