XmAb™2513, an Fc Engineered Humanized Anti-CD30 Monoclonal Antibody, Has Potent In Vitro and In Vivo Activities, and Has the Potential for Treating Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2340-2340 ◽  
Author(s):  
Chris E. Lawrence ◽  
Phil W. Hammond ◽  
Jonathan Zalevsky ◽  
Holly Horton ◽  
Seung Chu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Tumor Growth ◽  
Cynomolgus Monkey ◽  
Hematologic Malignancies ◽  
Repeat Dose ◽  
Dose Administration ◽  
Dose Study ◽  
Dependent Cell

Abstract XmAb2513 is a novel humanized monoclonal antibody (mAb) that binds to the human cell surface antigen CD30 and demonstrates anti-proliferative activity against CD30-positive (CD30+) cell lines. XmAb2513 also has an engineered Fc region to enhance cell killing activity via recruitment of effector cells through increased binding affinity to Fcγ receptors (FcγRs). Consequently, XmAb2513 exhibits superior antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP), when compared to a native IgG1 (unengineered) version of the antibody. To evaluate the potential clinical activity of XmAb2513 in CD30+ diseases such as Hodgkin Lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), XmAb2513 was tested in murine subcutaneous xenograft models of HL using the CD30+ L540 cell line. In the ICR-SCID mouse strain, intraperitoneal (ip) administration of XmAb2513 at 3 mg/kg every 4 days for 10 doses (q4d ×10), gave a statistically significant reduction in tumor growth and enhanced survival relative to the control. At doses of 10 and 30 mg/kg XmAb2513 (ip, q4d ×10) tumor growth was not only slowed, but elimination of established tumors was observed in 3/9 and 5/9 animals respectively. The treatment was well-tolerated. Preclinical studies were conducted to evaluate the safety and pharmacokinetics of XmAb2513 in large animals. In vitro studies demonstrated that the cynomolgus monkey was the appropriate species for study. Binding affinities of XmAb2513 to both human and cynomolgus monkey CD30 and FcγRs were evaluated by Biacore methods and were found to be similar. Additionally, fluorescein-XmAb2513 gave similar staining patterns in immunohistochemistry cross-reactivity studies with normal human and cynomolgus monkey tissue panels. As evidenced by in-life observations single (0, 1 and 100 mg/kg XmAb2513, intravenous [iv] infusion) and repeat dose (0, 10, 30 and 100 mg/kg XmAb2513, q5d ×6, iv infusion) treatment with XmAb2513 was well-tolerated. Serum cytokines showed no trend that was indicative of an XmAb2513-related effect following single dose administration. The pharmacokinetics of XmAb2513 was also determined after either single or repeat dose administration. In the repeat dose study (0, 3, 10 and 30 mg/kg XmAb2513, q5d ×6, iv infusion) exposure increased in a dose proportional manner, and terminal half-life (t1/2) ranged from 12–17 days. In the single dose study (0, 1 and 100 mg/kg XmAb2513, iv infusion) exposure was also proportional to dose. The exposure and t1/2 data support an every other week dosing interval in the clinic. These preclinical data provide a rationale for the clinical testing of XmAb2513 in patients with hematologic malignancies that express CD30, specifically HL and ALCL, and support the safety of repeat administration of XmAb2513 in humans.

scholarly journals A single intramuscular injection of monoclonal antibody MAD0004J08 induces in healthy adults SARS-CoV-2 neutralising antibody titres exceeding those induced by infection and vaccination

2021 ◽  
Author(s):  
Simone Lanini ◽  
Stefano Milleri ◽  
Emanuele Andreano ◽  
Sarah Nosari ◽  
Ida Paciello ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Geometric Mean ◽  
Healthy Adults ◽  
Post Treatment ◽  
Dose Escalation Study ◽  
Dose Administration ◽  
Single Dose Administration ◽  
Antibody Titres

Summary Background: The emerging threat represented by SARS–CoV–2 variants, demands the development of therapies for better clinical management of COVID–19. MAD0004J08 is an extremely potent Fc-engineered monoclonal antibody (mAb) able to neutralise in vitro all current SARS–CoV–2 variants of concern (VoCs). This ongoing study, evaluates safety, pharmacokinetics and SARS–CoV–2 sera neutralization effect of MAD0004J08 when administered as single dose intramuscularly in healthy adults. Method: We conducted a dose escalation study with sequential enrolment of three cohorts, each with an increasing dose level of MAD0004J08 (48mg, 100mg and 400mg). Within each cohort, 10 young healthy adults were randomized with 4:1 ratio to a single intramuscular (i.m.) injection of MAD0004J08 or placebo. The primary endpoint is the proportion of subjects with severe and/or serious treatment emergent adverse events (TEAEs) within 7 days post–treatment. Secondary endpoints reported in this paper are the proportion of subjects with solicited TEAEs up 7 days post dosing, MAD0004J08 serum concentrations and neutralising activity versus the original SARS-COV-2 Wuhan virus at different timepoints post-dosing. As post-hoc analyses, we compared the sera neutralising titres of subjects who received MAD0004J08 with those of people that had received the COVID–19 BNT162b2 mRNA vaccine in the previous sixty days (n=10) and COVID-19 convalescent patients (n=20), and assessed serum neutralisation activity against the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS–CoV–2 variants of concern. Findings: A total of 30 subjects, 10 per cohort, were enrolled and randomized. Data up to 30 days were available and analysed in this report. No severe TEAEs were reported in any of the cohorts in the 7 days post-treatment. MAD0004J08 was detected in the sera of treated subjects within few hours post-administration and reached almost maximal levels on day 8. The geometric mean neutralising titres (GMT) assessed against the original Wuhan virus peaked on day 8 and ranged 226 – 905, 905 – 2,560, and 1,280 – 5,120 for cohort 1, 2 and 3 respectively. The sera neutralising GMT in MAD0004J08 treated subjects in all the three cohorts were found to be 1·5– 54·5–fold higher compared to sera from convalescent patients and 1·83– 76·4–fold higher compared to sera from COVID-19 vaccinees. Finally, GMT in MAD0004J08 treated subjects showed high neutralising titres versus the B.1.1.7 (alpha), B.1.351 (beta) and B.1.1.248 (gamma) SARS-CoV-2 VoCs. Interpretation: A single dose administration of MAD0004J08 via i.m. route is safe and well tolerated and results in a rapid systemic distribution of the MAD0004J08 and sera neutralising titres higher than COVID–19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralise major SARS–CoV–2 variants of concern. Based on these results, a Phase 2-3 trial is ongoing to further assess the safety, dosage, and efficacy of MAD0004J08 in asymptomatic or mild-moderate symptomatic COVID–19 patients. Funding: EU Malaria Fund, Ministero dello Sviluppo Economico, Ministero della Salute, Regione Toscana, Toscana Life Sciences Sviluppo and European Research Council.

TSP-A74, a Novel Therapeutic Monoclonal Antibody Against TfR1 for Treatment of Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5214-5214
Author(s):  
Lilin Zhang ◽  
Fumiko Nomura ◽  
Youichi Aikawa ◽  
Yukio Sudo ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Tumor Growth Inhibition ◽  
Xenograft Models ◽  
Complete Tumor

Abstract Transferrin receptor 1(TfR1) is a type II transmembrane glycoprotein regulating the intracellular uptake of iron and is involved in cell growth, proliferation and survival. TfR1 is highly expressed on malignant cells, including those of hematologic malignancies. Therefore, TfR1 may be an attractive target for therapeutic monoclonal antibodies. We generated a panel of fully-human, anti-TfR1 monoclonal antibodies and evaluated the anti-tumor effects of these antibodies both in vitro and in vivo. The results led to the selection of TSP-A74, an antibody with potent in vitro and in vivo anti-tumor activity, for further evaluation in several hematologic malignancy models. First, the efficacy of TSP-A74 was evaluated in acute myeloid leukemia (AML) models. Two AML cell lines, Kasumi-1 and HL-60, were subcutaneously inoculated in severe combined immunodeficiency (SCID) mice. After the tumors were grown to a size of 150 mm3, TSP-A74 was administrated intravenously (IV) once weekly for 4 weeks at doses of 0.4, 2 and 10 mg/kg and 1, 3 and 10 mg/kg for the Kasumi and HL60 xenograft models, respectively. TSP-A74 demonstrated complete tumor regression in these two xenograft models at 10 mg/kg and complete tumor growth suppression in the Kasumi model at 2 mg/kg. Even at the low dose of 1 mg/kg, TSP-A74 demonstrated tumor growth inhibition (TGI) of 60% in the HL60 model. Next, the anti-tumor efficacy of TSP-A74 was assessed in an acute lymphoblastic leukemia (ALL) model. The ALL cell line, CCRF-CEM, was engrafted into SCID mice intravenously. After 3 days, TSP-A74 was administrated IV at a dose of 10 mg/kg once weekly for 4 weeks. The control mice (n=10) rapidly developed leukemia and none survived at 42 days after leukemia cell engraftment. However, 7 of 10 (70%) mice treated with TSP-A74 survived to 179 days after engraftment when the study was terminated. Finally, the efficacy of TSP-A74 was evaluated in non-Hodgkin's lymphoma subcutaneous xenograft models. TSP-A74 produced complete regression of established tumors in the SU-DHL-2 (diffuse large B-cell lymphoma) xenograft model at a dose of 3 mg/kg and tumor growth inhibition of 100 % in the HH (cutaneous T cell lymphoma) xenograft model at a dose of 10 mg/kg. These results indicate that the human anti-TfR1 monoclonal antibody, TSP-A74, could be a new therapeutic candidate for hematologic malignancies. Disclosures Zhang: Perseus Proteomics Inc.: Employment. Nomura:Perseus Proteomics Inc.: Employment. Aikawa:Perseus Proteomics Inc.: Employment. Sudo:Perseus Proteomics Inc.: Employment. Morishita:Perseus Proteomics Inc.: Research Funding.

scholarly journals Exploratory Pharmacokinetic/Pharmacodynamic and Tolerability Study of BCMAxCD3 in Cynomolgus Monkeys

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5668-5668 ◽  
Author(s):  
Suzette Girgis ◽  
Shoba Shetty ◽  
Trina Jiao ◽  
Chidozie Amuzie ◽  
Dan Weinstock ◽  
...  
Keyword(s):  
Single Dose ◽  
Cynomolgus Monkey ◽  
Bispecific Antibody ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Lymphoid Tissues ◽  
Repeat Dose ◽  
Dose Administration ◽  
Cynomolgus Monkeys ◽  
Dose Proportional

Abstract JNJ-64007957 is a bispecific antibody that binds to CD3 on T cells, and BCMA on plasma cells, and should induce T cell mediated killing of BCMA expressing malignant plasma cells. The objectives of this study were to characterize the tolerability of JNJ-64007957 when given intravenously as either single- or repeated-doses (5 total doses) to male cynomolgus monkeys. Pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in the repeat-dose groups; the single dose arms allowed for PK evaluations through Day 56, and determination of key PK parameters to support FIH dose modeling. Methods: The cynomolgus monkey was chosen for this study as JNJ-64007957 binds to both cynomolgus monkey CD3 and BCMA and it is an accepted non-rodent species for nonclinical tolerability, PK and PD evaluations. In this study, male monkeys (3/group) were administered either control or JNJ-64007957 via slow intravenous bolus injection on Days 1, 8, 15, 22, and 29 for repeat dose groups (1-4) and on Day 1 for single dose groups (5-6). The JNJ-64007957 doses were 0, 0.1, 1 and 10 mg/kg/week for repeat dose administration, and 1 or 10 mg/kg for single dose administration. Monkeys were evaluated for general tolerability, and samples were collected for PK and PD evaluations. Results: JNJ-64007959 was well tolerated upto 10 mg/kg. PK assessments showed that Cmax and AUC increased in a dose proportional manner, and the overall PK profiles suggested very low anti-drug antibody responses. For repeat dose groups, accumulation ratio was approximately 2. This supports dosing frequency of more than one week. There were no toxicologically significant findings in the monkeys at doses up to 10 mg/kg/week. Some minor changes in lymphoid cellularity were noted including an apparent slight to minimal and non-dose dependent decreases in plasma cells within one or more of the lymphoid tissues. There were no changes in peripheral blood lymphocytes or cytokine release. The small number of animals in this study precludes making definitive conclusions regarding the pharmacodynamics effects of dual BCMA and CD3 engagement but this will be investigated in a larger study that will support first in human dosing. Conclusions: Overall, this exploratory cynomolgus monkey study was designed to evaluate JNJ-64007957 tolerability and PK/PD in one study. This study indicated that a BCMAxCD3 bispecific antibody showed no toxicologically significant effects when administered to monkeys once per week for 5-weeks and exposure was dose proportional. Disclosures Girgis: Janssen Research & Development: Employment. Shetty:Janssen Research & Development: Employment. Jiao:Janssen Research & Development: Employment. Amuzie:Janssen Research & Development: Employment. Weinstock:Janssen Research & Development: Employment. Grimme Watson:Janssen Research & Development: Employment. Ford:Janssen Research & Development: Employment. Pillarisetti:Janssen: Employment. Baldwin:Janssen: Employment. Bellew:Janssen: Employment.

scholarly journals hLL2-Cys-PBD, a New Site-Specifically Conjugated, Pyrrolobenzodiazepine (PBD) Dimer-Based Antibody Drug Conjugate (ADC) Targeting CD22-Expressing B-Cell Malignancies.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4176-4176 ◽  
Author(s):  
Francesca Zammarchi ◽  
Simon Corbett ◽  
Lauren Adams ◽  
Maria Mellinas-Gomez ◽  
Peter Tyrer ◽  
...  
Keyword(s):  
Single Dose ◽  
B Cell ◽  
Cynomolgus Monkey ◽  
Research Funding ◽  
Employment Equity ◽  
Dose Study ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract We previously described the development of hLL2-PBD, an ADC composed of the humanized monoclonal antibody epratuzumab (hLL2) against human CD22, stochastically conjugated to SG3249, a cathepsin B-cleavable valine-alanine PBD payload. SG3249, also known as tesirine, is a potent and clinically validated PBD payload currently being employed in the clinic in three ADCs: the CD25-targeted ADCT-301, the CD19-targeted ADCT-402, both for the treatment of lymphoma and leukemia, and the DDL3-targeted rovalpituzumab tesirine for the treatment of small cell lung cancer. hLL2-PBD demonstrated potent and specific in vitro and in vivo activity in the CD22-positive human Burkitt's lymphoma-derived cell lines Ramos, Daudi and WSU-DLCL2. Here, we describe the development and pre-clinical characterization of hLL2-cys-PBD, an ADC composed of an engineered version of epratuzumab (hLL2-cys), site-specifically conjugated to the PBD payload tesirine. The average drug to antibody ratio of hLL2-cys-PBD is 1.74. In vitro, hLL2-cys-PBD showed potent and specific cytoxtoxic activity against a panel of CD22-expressing human lymphoma cell lines, including Ramos, Daudi, WSU-DLCL2 and SU-DHL-4. Moreover, hLL2-cys-PBD was efficiently internalized by CD22-expressing cells and, consistent with the proposed mode of action of PBD dimer warheads, it induced DNA inter-strand cross-linking after a two hour exposure period, as measured by the modified single cell gel electrophoresis (comet) assay. In contrast, a non-CD22-targeted, site-specific, PBD-containing control ADC did not yield appreciable DNA cross-links. In vivo, hLL2-PBD showed potent, dose-dependent, and durable anti-tumor activity in subcutaneously implanted Ramos and WSU-DLCL2 xenograft models. In the Ramos model, a single dose of hLL2-cys-PBD at 1 mg/kg induced complete regression (CR) in all ten treated mice, with 9/10 tumor free survivors (TFS) at the end of the study on day 60. In the WSU-DLCL2 model, a single dose of hLL2-cys-PBD at 3 mg/kg resulted in 3/10 partial regression, 7/10 CR and 2/10 TFS at the end of the study on day 60. The toxicity of hLL2-cys-PBD was evaluated in rat (single dose study) and in cynomolgus monkey (repeat dose study). In rat, hLL2-cys-PBD was well tolerated at 2 mg/kg. In cynomolgus monkey, hLL2-cys-PBD elicited the expected rapid B-cell depletion and it was well tolerated at 0.6 mg/kg. Together, these data demonstrate that hLL2-cys-PBD has potent anti-tumor activity against CD22-expressing hematological tumors and warrants further development of this ADC into the clinic. Disclosures Zammarchi: ADC Therapeutics: Employment. Corbett:ADC Therapeutics: Research Funding. Adams:Medimmune: Employment. Mellinas-Gomez:Medimmune: Employment. Tyrer:Medimmune: Employment. Dissanayake:ADC Therapeutics: Employment. Sims:ADC Therapeutics: Employment. Havenith:ADC Therapeutics: Employment. Chivers:ADC Therapeutics: Employment. Willimas:MedImmune: Employment. Howard:MedImmune/ ADC Therapeutics: Employment, Equity Ownership, Patents & Royalties. Hartley:Spirogen Ltd/ADC Therapeutics: Employment, Equity Ownership, Research Funding. van Berkel:ADC Therapeutics: Employment, Equity Ownership, Patents & Royalties.

scholarly journals In VitroAssessment of the Immunological Significance of a Human Monoclonal Antibody Directed to the Influenza A Virus Nucleoprotein

2013 ◽  
Vol 20 (8) ◽  
pp. 1333-1337 ◽  
Author(s):  
Rogier Bodewes ◽  
Martina M. Geelhoed-Mieras ◽  
Jens Wrammert ◽  
Rafi Ahmed ◽  
Patrick C. Wilson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Influenza A Virus ◽  
Influenza A ◽  
Viral Antigen ◽  
Human Monoclonal Antibody ◽  
Cell Cytotoxicity ◽  
Influenza A Viruses ◽  
Dependent Cell ◽  
Infected Cells

ABSTRACTInfluenza A viruses cause annual epidemics and occasionally pandemics. Antibodies directed to the conserved viral nucleoprotein (NP) may play a role in immunity against various influenza A virus subtypes. Here, we assessed the immunological significance of a human monoclonal antibody directed to NPin vitro. This antibody bound to virus-infected cells but did not display virus-neutralizing activity, complement-dependent cell cytotoxicity, or opsonization of viral antigen for improved antigen presentation to CD8+T cells by dendritic cells.

HCD122, an Antagonist Human Anti-CD40 Monoclonal Antibody, Enhances Efficacy of CHOP in Tumor Xenograft Model of Human Diffuse Large B-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 528-528 ◽  
Author(s):  
Mohammad Luqman ◽  
Ssucheng J. Hsu ◽  
Matthew Ericson ◽  
Sha Klabunde ◽  
Seema Kantak
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract HCD122 (formerly known as CHIR-12.12), is a fully human anti-CD40 monoclonal antibody (mAb) currently in Phase I clinical trials for treatment of chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). An IgG1 antibody selected for its potency as an antagonist of the CD40 signaling pathway, HCD122 both inhibits CD40/CD40L-stimulated growth of lymphoma cells ex vivo, and mediates highly effective Antibody Dependent Cell-mediated Cytotoxicity (ADCC) in vitro. As a single agent, HCD122 exhibits potent anti-tumor activity in vivo, in preclinical models of MM, Hodgkin’s lymphoma, Burkitt’s lymphoma, mantle cell lymphoma and diffused large B-cell lymphoma (DLBCL). Although several therapeutic antibodies approved for treatment of Non-Hodgkin’s Lymphoma have clinical activity as single agents, combining these antibodies with standard-of-care chemotherapeutic regimens such as CHOP (cytoxan, vincristine, doxorubicin and prednisone) is proving optimal for both increasing response rates and extending survival, and antibodies currently in clinical development are likely to be used in combination therapies in the future. Therefore the studies reported here examine the effects of combining HCD122 with CHOP, the standard for treatment of high grade NHL, in in vitro and in vivo models of DLBCL. In the xenograft RL model of DLBCL, HCD122 administered intraperitoneally weekly at 1 mg/kg as a single agent, or in combination with CHOP (H-CHOP), and CHOP alone all significantly reduced tumor growth at day 25 when compared to treatment with huIgG1 control antibody (P<0.001). However, tumor growth delay (time to reach tumor size of 500 mm3) was significantly longer for H-CHOP (17.5 days), than for CHOP (8 days) or HCD122 (6 days) (p < 0.001). No toxicity was observed with the H-CHOP combination. Interestingly, at the end of the study (day 35), reduction in tumor growth was significantly greater in the treatment group that received H-CHOP than the groups that received either 10 mg/kg Rituxan plus CHOP (R-CHOP) (p < 0.05) or CHOP alone (p < 0.001). These data show that in this model, treatment with the combination H-CHOP results in greater anti-tumor efficacy than with either modality alone or R-CHOP. We have observed that in vitro, exposure to CD40 Ligand (CD40L) results in aggregation of DLBCL cells, and postulate that interfering with the ability of cancer cells to adhere and interact with each other and their microenvironment may potentiate the effect of chemotherapeutics. To elucidate the mechanism by which the combination of HCD122 and CHOP enhanced efficacy in vivo, we developed an in vitro system to examine the effects of HCD122 on the expression of adhesion molecules in the RL and SU-DHL-4 cell lines. In these studies, HCD122 inhibited CD40L-induced expression of CD54, CD86 and CD95 in both cell lines, as well as aggregation of SU-DHL-4 cells. The combined effect of each of the components of CHOP with HCD122 in three-dimensional spheroid cultures is currently under investigation. These data provide a therapeutic rationale for combination of HCD122 with CHOP in DLBCL clinical trials.

A phase I, first-in-human study of ARGX-110, a monoclonal antibody targeting CD70, a receptor involved in immune escape and tumor growth in patients with solid and hematologic malignancies.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Ahmad Awada ◽  
Christian D. Rolfo ◽  
Sylvie Rottey ◽  
Laure Ysebrant de Lendonck ◽  
Wilfried A. Schroyens ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Phase I ◽  
Immune Escape ◽  
Human Study ◽  
Hematologic Malignancies ◽  
Antibody Targeting

Inhibition of tumor growth in vitro and in vivo by a monoclonal antibody against human chorionic gonadotropin β

2007 ◽  
Vol 114 (2) ◽  
pp. 94-102 ◽  
Author(s):  
Ning Yu ◽  
Wei Xu ◽  
Zhenggang Jiang ◽  
Qinghua Cao ◽  
Yiwei Chu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Inhibition Of Tumor Growth

scholarly journals Combination of Loncastuximab Tesirine and Polatuzumab Vedotin Shows Increased Anti-Tumor Activity in Pre-Clinical Models of Non-Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2273-2273
Author(s):  
Nikoleta Sachini ◽  
Asma Jabeen ◽  
Patrick H van Berkel ◽  
Francesca Zammarchi
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Hodgkin Lymphoma ◽  
Annexin V ◽  
Publicly Traded ◽  
Non Hodgkin Lymphoma ◽  
Clinical Models ◽  
Anti Tumor Activity

Abstract Loncastuximab tesirine-lpyl (formerly ADCT-402) is an antibody-drug conjugate (ADC) comprising a humanised anti-CD19 monoclonal antibody conjugated to the pyrrolobenzodiazepine (PBD) dimer-based payload tesirine. Once bound to CD19 on the cell membrane, loncastuximab tesirine is rapidly internalised and the released PBD dimer warhead causes interstrand DNA crosslinks which ultimately trigger cell death. Pre-clinically, loncastuximab tesirine has shown potent and specific anti-tumor activity in lymphoma models both as single agent and in combination with other approved drugs, like venetoclax, idelalisib and bendamustine (Zammarchi, Corbett et al. 2018, Tarantelli, Spriano et al. 2019). Loncastuximab tesirine has been recently approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and it is currently being tested in multiple clinical trials, either as monotherapy or in combination with other anti-lymphoma drugs. Polatuzumab vedotin is an ADC composed of a humanized anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (vcMMAE) and it is approved by the FDA for treatment of r/r DLBCL when used in combination with bendamustine and rituximab. Here, we investigated the in vitro and in vivo anti-tumor activity of loncastuximab tesirine combined with polatuzumab vedotin in pre-clinical models of non-Hodgkin lymphoma (NHL). In vitro, the combination of loncastuximab tesirine and polatuzumab vedotin was tested in three human-derived, CD19 and CD79b-positive NHL cell lines (WSU-DLCL2, TMD8 and Ramos) and it resulted in synergistic (TMD8 and Ramos) and additive (WSU-DLCL2) activity, as assessed by the Chou-Talalay method. Quantification of cell viability (propidium iodide [PI]-negative and Annexin V-negative) and early/late apoptosis (Annexin V-positive and PI-negative/ Annexin V-positive and-PI positive) on TMD8 and Ramos cells treated with loncastuximab tesirine, polatuzumab vedotin or the combination of the two agents showed a significant reduction of viable cells accompanied by an increase in apoptotic cells in the combination setting compared to the single agents. In vivo, loncastuximab tesirine was tested either alone (0.25 or 0.5 mg/kg, single dose) or in combination with polatuzumab vedotin (1 mg/kg, single dose) in the WSU-DLCL2 xenograft model. At the highest dose of loncastuximab tesirine, combination with polatuzumab vedotin resulted in improved anti-tumor activity and superior response rate compared to the 2 agents in monotherapy. All treatment regimens were well tolerated by the mice, as assessed by body weight measurements and frequent observation for signs of treatment-related side effects. In conclusion, the combination of loncastuximab tesirine and polatuzumab vedotin resulted in improved anti-tumor activity both in vitro and in vivo in lymphoma preclinical models and it was well tolerated. Altogether, these novel pre-clinical data warrant translation of the combination of loncastuximab tesirine and polatuzumab vedotin into the clinic for the treatment of NHL. Disclosures Sachini: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jabeen: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. van Berkel: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Zammarchi: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

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