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PEER-REVIEWED ARTICLES

First Patient Dosed in Phase Ib Clinical Trial of Camidanlumab Tesirine in Patients with Advanced Solid Tumors

A first patient has been dosed in Phase Ib clinical trial of camidanlumab tesirine, also know ADCT-301, a proprietary antibody-drug conjugate or ADC being developed by ADC Therapeutics, for the treatment of patients with advanced solid tumors.[1]

The Phase Ib clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of camidanlumab tesirine in patients with selected solid tumors that are locally advanced or metastatic.

Camidanlumab tesirine is an antibody-drug conjugate composed of HuMax®-TAC (licensed from Genmab), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin.

The HuMax-TAC monoclonal antibody targets the cell-surface antigen CD25 (the alpha chain of the Interleukin-2 receptor or IL2R-α) which is over-expressed on a variety of hematological tumors and shows limited expression on normal tissues.

IL2R-α [*], one of a heterotrimer that makes up the IL2R, has been recognized to play an important role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection. [2] Scientists have also confirmed the preponderance of CD25+ cells in hematological malignancies (malignant lymphomas including B-cell malignancies) [3] and the relationship between increased CD25 expression and poor prognosis [4] raising the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these cells in vivo.

Once bound to a CD25-expresing cell, the investigational agent is internalized into the cell where enzymes release the PBD-based payload. The intra-tumor release of its PBD payload may cause bystander killing of neighboring tumor cells. In addition, the PBD payload will trigger immunogenic cell death, which in turn will strengthen the immune response against tumor cells.

Camidanlumab tesirine is already being evaluated in relapsed and refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).[1][5]

American Society of Hematology
At the 2018 American Society of Hematology (ASH) Annual Meeting, ADC Therapeutics presented interim data on 113 patients dosed in its Phase Ia/Ib clinical trial in lymphoma. In hodgkin lymphoma patients with a median of five prior lines of therapy and no other approved therapy options, the overall response rate was 86.5%, including a 43% complete response rate, at the dose being considered for a pivotal Phase II clinical trial that the Company anticipates initiating in 2019.

“We continue to be very encouraged by the anti-tumor activity of [camidanlumab tesirine] in Hodgkin lymphoma and non-Hodgkin lymphoma,” said Jay Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics/

“In addition, based on the immune-oncology potential [camidanlumab tesirine] has demonstrated in preclinical studies, we are excited to be starting this clinical trial for ADCT-301 in solid tumors to see if we can make an impact and improve patient outcomes in multiple difficult-to-treat solid tumor cancers,” Feingold added.

Solid Tumors
At the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting, ADC Therapeutics presented preclinical data showing that an engineered version of camidanlumab tesirine demonstrated highly potent anti-tumor activity, both as a monotherapy and in combination with a checkpoint inhibitor, in multiple solid tumor models with infiltrating CD25-positive regulatory T cells (Tregs).

“[Camidanlumab tesirine] targets CD25, which is expressed on Tregs that infiltrate the local tumor environment,” noted Patrick van Berkel, PhD, Senior Vice President of Research and Development at ADC Therapeutics.

“In preclinical models, a single dose of the CD25-targeted ADC induced strong and durable anti-tumor activity against established CD25-negative solid tumors with infiltrating Tregs both as a monotherapy and in combination with a checkpoint inhibitor. Moreover, re-challenged mice did not develop new tumors indicating the CD25-targeted ADC was able to induce tumor-specific protective immunity,” Van Berkel, Ph.D, added.

The Phase Ib trial of camidanlumab tesirine in patients with advanced solid tumors has both dose escalation and cohort expansion parts. The dose escalation part is designed to establish a safe and tolerated dose and dosing schedule of camidanlumab tesirine in these patients.

The identified dose and dosing schedule will be studied in the dose expansion part. Approximately 50 patients will be enrolled in the trial.

Reference
[1] Study of ADCT-301 in Patients With Selected Advanced Solid Tumors – NCT03621982
[2] Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol Lett. 2007 Nov 30;114(1):1-8. Epub 2007 Sep 14.
[3] Srivastava MD, Srivastava A, Srivastava BI. Soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in hematologic malignancies. Leuk Lymphoma. 1994 Jan;12(3-4):241-51.
[4] Yoshida N, Oda M, Kuroda Y, Katayama Y, Okikawa Y, Masunari T, Fujiwara M, Nishisaka T, et al. Clinical significance of sIL-2R levels in B-cell lymphomas. PLoS One. 2013 Nov 13;8(11):e78730. doi: 10.1371/journal.pone.0078730. eCollection 2013.
[5] Study of ADCT-301 in Patients With Relapsed or Refractory Hodgkin and Non-Hodgkin Lymphoma – NCT02432235 


[*] The interleukin-2 (IL-2) receptor includes three different IL-2 receptor chains: α, β, and γ. Among these, the α-chain (CD25) on the cell membrane is cleaved by proteolytic processing, and the cleaved α-chain is detected as sIL-2R. The ligand of IL-2R, IL-2, plays a critical role in the development of T and NK lymphocyte as a growth factor.


Last Editorial Review: January 7, 2019

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Study Evaluates Pyrrolobenzodiazepine (PBD)-dimers Containing Disulfide-based Prodrugs as Payloads for Antibody-Drug Conjugates

A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro in the presence of either glutathione (GSH) or cysteine (Cys).

Pyrrolobenzodiazepines, a class of natural products produced by various actinomycetes (a broad group of bacteria that form thread-like filaments in the soil and are responsible for the distinctive scent of freshly exposed, moist soil), are sequence selective DNA alkylating compounds with significant antitumor properties. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs. Some PBDs have the ability to recognize and bond to specific sequences of DNA.

Good correlation
In the study, researchers observed a good correlation between in vitro GSH stability and in vitro cytotoxicity toward tumor cell lines. The prodrug-containing compounds were typically more potent against cells with relatively high intracellular GSH levels (e.g., KPL-4 cells). Several antibody-drug conjugates (ADCs) were subsequently constructed from pyrrolobenzodiazepine (PBD) dimers that incorporated selected disulfide-based prodrugs.[1]

Such HER2 conjugates exhibited potent antiproliferation activity against KPL-4 cells in vitro in an antigen-dependent manner.

Unstable
However, the disulfide prodrugs contained in the majority of such entities were surprisingly unstable toward whole blood from various species. One HER2-targeting conjugate that contained a thiophenol-derived disulfide prodrug was an exception to this stability trend.

It exhibited potent activity in a KPL-4 in vivo efficacy model that was approximately 3-fold weaker than that displayed by the corresponding parent ADC. The same prodrug-containing conjugate demonstrated a 3-fold improvement in mouse tolerability properties in vivo relative to the parent ADC which did not contain the prodrug.


Last Editorial Review: July 31, 2018

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Anti-CLL-1 ADC May Offer Effective and Safe Treatment Options for Patients with AML

Over the last 40 years treatment of acute myeloid leukemia or AML has not significantly changed.

Today, the standard of care for AML is treatment with cytarabine, also known as cytosine arabinoside or ara-C and anthracycline‑based chemotherapy induction regimens including drug such as daunorubicin (daunomycin) or idarubicin and sometimes a third drug, cladribine (Leustatin, 2-CdA).

The re-approval of gemtuzumab ozogamicin (Mylotarg®; Pfizer), an anti-CD33-calicheamicin antibody-drug conjugate or (ADC), has demonstrated that targeted agents like ADCs offer a clinically validated option to enhance the effectiveness of induction therapy.

Gemtuzumab ozogamicin targets CD33, a 67-kDa type I transmembrane receptor. Based on its broad expression on AML blasts, is target seems appropriate. However, researchers have found that the expression of CD33 on normal hematopoietic stem cells (HSCs) indicates that prolonged cytopenias among multiple hematopoietic lineages may limit the clinical benefit of CD33 targeting agents.

C-type lectin-like molecule-1
Now, following the initial success of gemtuzumab ozogamicin, researchers at Genentech interested in developing a next generation of ADCs for the treatment of AML, are investigating the expression pattern of C-type lectin-like molecule-1 or CLL-1 and its hematopoietic potential were investigated.[1]

They developed a novel anti-CLL-1-ADC which includes a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker. The efficacy and safety profiles of this ADC were evaluated in mouse xenograft models and in cynomolgus monkeys.

The results of their experimental development were published in the June 2018 issue of Clinical Cancer Research,

As part of their research process, Bing Zheng, Shang-Fan Yu and colleagues first validated CLL-1, a leukemic stem cell marker as a target for AML treatment as compared to CD33.

The researchers analyzed the surface expression of CLL-1 and CD33 on AML blasts from samples obtained from 70 patients with AML using flow cytometry. CLL-1 exhibited similar frequency as compared to CD33 on AML blasts. Their analysis of CLL-1 on bone marrow samples from patients with AML demonstrated expression on CD34 AML blasts but not on lymphocytes or platelets.

Furthermore, CLL-1 expression was also not detected on CD34+/CD38- stem cells obtained from healthy donors. This shows, according to the researchers, that CLL-1 shares similar prevalence and trafficking properties that make CD33 an effective target for AML. But more importantly, CLL-1 lacks the expression of hematopoietic stem cells that may be hampering current CD33 and CD123 targeted ADCs.

Hematopoietic potential
Next, the researchers evaluated the hematopoietic potential of CLL-1. To identify the stage at which CLL-1 expression begins during hematopoiesis, the investigators used a panel of markers to define each differential stage of CD34+ normal hematopoietic stem cells and progenitor cells (HSPCs).

The study shows that CLL-1 was expressed on at least half of the population of CD34+/CD38+/CD10-/CD45RA-/CD135+ common myeloid progenitor (CMP) cells. CLL-1 was also expressed in increased levels on CD34+/CD38+/CD10-/CD45RA+/CD135+ granulocyte-monocyte progenitor (GMP) cells.

CLL-1 expression was lost on the next differentiated cells, megakaryocyte-erythroid progenitor, thus indicating that CLL-1 is an, as the researchers explain, an early myeloid lineage marker that resides during the differentiation from CMP to GMP cells.

Using colony forming assay, also known as clonogenic assay, the researchers showed that depletion of CD34+/CLL1+ progenitor cells does not impair the normal hematopoietic potential or induce persistent thrombocytopenia.

Conjugation
During the next step in their research, the researchers developed a novel anti-CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker.

They evaluated the efficacy and safety profiles of their anti-CLL-1 ADC in three mouse xenograft tumor models and in Cynomolgus monkeys. These models expressed CLL-1 at levels within the range observed in patients with AML, with cytogenetic features of the disease typically shown in patients with a poor prognosis. In compared to controls, the anti-CLL-1 ADC demonstrated clear dose-dependent inhibition of tumor growth in mouse models.

Finally, the researchers evaluated the target-dependent tolerability and toxicity of anti-CLL-1 ADC in Cynomolgus monkeys.

A single IV dose of 0.1 and 0.2 mg/kg of anti-CLL1 ADC, was tolerated.  The results showed a slight decrease in the numbers of granulocytes (neutrophils, eosinophils, basophils) and monocytes. This was reached a limit on days 8–12 after treatment and recovered at day 14/15 (monocytes and basophils) or day 22 (neutrophils). A key observation was that cells that lack CLL-1 expression, including lymphocytes, were unaffected by treatment with the novel anti-CLL-1 ADC.

The data suggest that a novel anti-CLL-1 ADC may offers the potential of becoming a highly effective, and safer treatment option for patients with AML. By reducing and allowing for faster recovery from initial cytopenias, the novel treatment option resolves some limitations of the current generation of antibody-drug conjugates.


Last Editorial Review: July 1, 2018

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Copyright © 2018 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Interim Phase I Data from Camidanlumab Tesirine (ADCT-301) Shows Encouraging Preliminary Safety and Efficacy Results

Clinical data from two ongoing Phase I clinical trials evaluating camidanlumab tesirine, also known as ADCT-301* or “Cami-T”, in important subtypes of lymphoma and leukemia show encouraging, preliminary, safety and efficacy results.

The data from these clinical trials was presented at the 59th annual meeting of the American Society of Hematology (ASH), held December 9 – 12, 2017 in Atlanta, Georgia (USA).

Mode of Action
Camidanlumab tesirine is an antibody-drug conjugate or ADC, being developed by ADC Therapeutics, comprising a human monoclonal antibody against CD25 (HuMax®-TAC, licensed from Genmab), stochastically conjugated through a dipeptide cleavable linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin with a drug-antibody ratio (DAR) of 2.3 [1][2]

Once bound to a CD25-expresing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. After internalizing, the released pyrrolobenzodiazepine (PBD) dimer payload, found among the most cytotoxic agents known, binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. [2] In turn, this eventually results in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis.


Acute myeloid leukemia is the most common leukemia in the adult population in United States. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis.

Camidanlumab tesirine … has shown an acceptable safety profile…


In vivo, single dose of camidanlumab tesirine leads to dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models.[2]

Attractive target
CD25, also known as interleukin-2 receptor alpha or IL2R-α, a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin-2 or IL-2, is an attractive target for an antibody-drug conjugate approach as it is expressed on the cell surface of a wide range of hematological malignancies, including Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma lymphoma. Interestingly, the expression of CD25 in healthy organs is restricted. [3][4]

To date, camidanlumab tesirine is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma, and in patients with relapsed or refractory CD25-positive acute myeloid leukemia and acute lymphoblastic leukemia. [5][6]

Poster 1.0: Presented at the 59th (2017) Annual Meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma. Click here to enlarge.

B-cell Hodgkin’s or non-Hodgkin’s lymphoma
The first poster presentation (1510) showed data from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies.

Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks. [7]

“Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77% overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44% complete response rate,” noted Steven M. Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator of the study.

“We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33%) and B-cell lymphomas (ORR: 19%). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II,” Horwitz added.

Key findings included:

  • For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44%) and 9 patients achieving a partial response (33%).
  • For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50%).
  • For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77%), 13 of 18 patients previously treated with a checkpoint inhibitor (72%), 9 of 14 patients who had previously undergone a stem cell transplantation (64%), and 4 of 8 patients who had previously received all three of these treatments (50%).

Adverse events.
Camidanlumab tesirine has been reasonably well tolerated.

The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30%), rash (26%), elevated gamma-glutamyltransferase (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13%), reduced platelet count (9%), elevated alanine aminotransferase (6%), anemia (6%), and rash (6%). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.

Based on the encouraging preliminary safety and efficacy results, the researchers support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.

Poster 2.0: Presented at the 59th (2017) Annual meeting of the American Society of Hematology. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia. Click here to enlarge.

B-cell acute myeloid leukemia or acute lymphoblastic leukemia
Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit.

The median age of patients was 67 years and they had a median of 3 prior therapies.[8]

In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings:

  • One patient achieved a complete response with incomplete blood count recovery;
  • Camidanlumab tesirine has shown an acceptable safety profile
  • The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30%), nausea (24%), febrile neutropenia (21%), and pneumonia (21%). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21%), thrombocytopenia (15%), fatigue (12%), reduced neutrophil count (12%), and pneumonia (12%);
  • Dose escalation will continue to investigate weekly dosing.

Earlier this year interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, were presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirming  favorable tolerability and efficacy.

These results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL). [9]


* Also see: ADC Review | Antibody-drug Conjugates – Drug map

Last editorial review: December 16, 2017

Featured Image:  ADC Therapeutics Booth | 59th Annual Meeting of the American Society of Hematology. Courtesy: © 2017. Sunvalley Communication/Evan Wendt |Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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First Clinical Data from ADCT-402 Demonstrates Encouraging Antitumor Activity in r/r non-Hodgkin Lymphoma

The first clinical data from an ongoing Phase I clinical trial evaluating ADCT-402 for the treatment of relapsed or refractory non-Hodgkin’s lymphoma has been presented at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 in Lugano, Switzerland. [1]

ADCT-402, a novel antibody-drug conjugate or ADC, is composed of a humanized monoclonal antibody that binds to human CD19, conjugated to a highly potent proprietary pyrrolobenzodiazepine (PBD) dimer toxin. The drug is being developed by ADC Therapeutics.

The PBD-based payload has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and resulting in cell death.

CD19 clinically validated target, highly expressed in a wide range of B-cell hematological tumors, including certain forms of lymphomas and leukemias, while its expression in healthy tissues is restricted.

Immune system
Lymphoma is a cancer that begins in cells of the immune system, in particular in the lymph system. The lymph is rich in lymphocytes, a type of white blood cells that help the body fight off infections and other diseases. Lymphoma develops when lymphocytes become cancerous which can occur in both children and adults. The two main types of lymphomas are Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL), and are differentiated by the type of lymphocytes affected and their appearance under the microscope.

According to the National Cancer Institute around 72,000 new people are diagnosed with non-Hodgkin lymphoma in the United States and around 9,000 new people are diagnosed with Hodgkin lymphoma.

Interim trial results
The interim results from the Phase I, open label, dose-escalating study of ADCT- 402 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory non- Hodgkin’s lymphoma (r/r NHL) were reported. Data were presented from 62 evaluable patients with a median age of 67 years and 3 previous therapies.

Treatment emergent adverse events
Among the patients enrolled at the time of the data cutoff for presentation, ADCT-402 has been reasonably well tolerated with the most common treatment emergent adverse events or TEAEs being fatigue, neutropenia and thrombocytopenia which have been treated symptomatically and, in some cases, with dose delays, reductions and discontinuation. The overall response rate with doses 120μg/kg was 61% in the total patient population and 57% in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL). The maximum tolerated dose has not yet been reached.

“These clinical data provide additional support for the efficacy and tolerability of ADCT-402, as well as of our ADC technology platform based on PBD-warheads,” noted Jay Feingold, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“In preclinical studies the PBD dimer toxin has been shown to be a highly potent killer of cancer cells even in hard to treat tumors. The presented results confirm the potential role of ADCT-402 in the treatment of relapsed and refractory non-Hodgkin’s lymphoma. We believe these findings reflect a strong path forward and we are looking forward to getting further results later this year,” he added.

Encouraging findings
“These early findings are very encouraging as they demonstrate a clear clinical benefit and manageable toxicity for patients who failed, or are intolerant to any established therapy” said principal investigator Brad Kahl, M.D. Professor for Medical Oncology at the Washington University School of Medicine in St. Louis.

“With the impressive activity already observed at low doses, we look forward to continuing this study to further identify the maximum tolerable dose and provide a preliminary assessment of its single-agent anti-tumor activity and toxicity profile. The promising overall response seen in specific non-Hodgkin’s lymphoma subtypes leads us to also further evaluate the drug candidate in diffuse large B-cell lymphoma,” Kahl observed.

In addition to the ongoing Phase I trial, ADCT-402 is currently being evaluated in an ongoing Phase I clinical trial in Acute Lymphoblastic Leukemia (ALL). ADC Therapeutics has four PBD-based antibody drug conjugates in six ongoing Phase I clinical trials in the USA and in Europe.


Last editorial review: June 16, 2017

Featured Image: Lugano, Switzerland. Courtesy: © 2017 Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland Used with permission.

Copyright © 2017 InPress Media Group, LLC. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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U.S. FDA Lifts Clinical Hold Phase I Trials of Vadastuximab Talirine

The U.S. Food and Drug Administration (FDA) confirmed today that it has lifted the clinical hold on phase 1 trials of vadastuximab talirine (SGN-CD33A; 33A) in acute myeloid leukemia (AML). The clinical hold was announced on December 27, 2016.

Vadastuximab talirine is a novel investigational antibody-drug conjugate or ADC targeted to CD33 utilizing Seattle Genetics’ proprietary technology. CD33 is expressed on most acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) blast cells. The CD33 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine or PBD dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD33-expressing cells.

Orphan Drug Designation
Vadastuximab talirine was granted Orphan Drug Designation by both the FDA and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.

“The clinical hold on early-stage vadastuximab talirine clinical trials has been resolved through a comprehensive analysis of the clinical data from over 300 patients treated to date, evaluation by an independent committee of clinical experts, collaborative interactions with the FDA, and protocol amendments designed to further enhance patient safety,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“We will resume two phase I trials in AML and plan to initiate a randomized phase II trial during 2017 evaluating vadastuximab talirine in combination with standard of care chemotherapy in frontline, younger AML patients. In addition, we are continuing to enroll our ongoing phase 3 randomized CASCADE trial in frontline older AML patients and our phase I/II trial in frontline high-risk myelodysplastic syndrome (MDS).”

Resuming trials
Following the lifting of the clinical hold, Seattle Genetics will resume two phase I trials of vadastuximab talirine. The first is combination treatment with standard of care, or 7+3, chemotherapy in newly diagnosed younger AML patients. The second is monotherapy and combination treatment with hypomethylating agents in both newly diagnosed and relapsed AML patients.

However, the company will not resume the phase I/II trial of vadastuximab talirine monotherapy in pre- and post-allogeneic transplant AML patients given the challenges of developing therapies in this specific setting.

The randomized global phase III CASCADE trial in frontline older AML and phase I/II trial in frontline MDS were not placed on clinical hold and have continued to enroll patients. Planned studies include a randomized phase II trial of vadastuximab talirine in combination with 7+3 chemotherapy in frontline younger AML patients.

As part of resuming the clinical trial program, additional risk mitigation measures will be implemented in all vadastuximab talirine clinical studies, including revised eligibility criteria and stopping rules for veno-occlusive disease (VOD), which occurs when the small blood vessels that lead into and are inside the liver become blocked.


Last Editorial Review: March 6, 2017

Featured Image: Scientists at Seattle Genetics. Courtesy: © 2017 Seattle Genetics. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Novel Cancer Therapeutics Drive Therapy Market

An increased need for better cancer treatment continues to boost the global cancer biological therapy market. According to a report published by Global Market Insights, cancer biological therapy market size is expected to reach US $ 100 billion by 2023, at upwards of 6% growth from 2016 to 2023.

Although research and development continues to break major boundaries in how we understand and fight cancer, the unfortunate truth is that each year there are still more than eight million lives lost to the disease. What’s more, in some areas, the number of new cases is growing. And this rising number of new cancer cases combined with a growing global geriatric population are considered as two major factors that drive the demand for cancer therapies. Furthermore, rising awareness of the effectiveness of biological therapies also contributes to the expanding industry.


“… A rising awareness of the effectiveness of biological therapies …contributes to the expanding industry, which is expected to reach US $ 100 billion by 2023”


According to the report, U.S. still dominates the North American cancer biological therapy market, accounting for over 80% of the revenue in 2015. Increased public funding for R&D and other government initiatives are expected to drive growth in the United States. In Europe, Germany is the largest player in the market due to increased prevalence and favorable public reimbursement and insurance policies. While demand for biological therapy in the Asia Pacific is driving by Japan and China.

Global Market Insights lists a number of companies with interesting R&D programs.

Innovative targeted therapies
Actinium Pharmaceuticals, a biopharmaceutical company developing innovative targeted therapies for cancers lacking effective treatment options. The company’s proprietary platform utilizes monoclonal antibodies to deliver radioisotopes directly to cells of interest in order to kill those cells safely and effectively.

lomab-B is Actinium’s lead product candidate that is currently being studied in a 150-patient, multicenter pivotal Phase III clinical trial in patients with relapsed or refractory acute myeloid leukemia who are age 55 and above. Upon approval, Iomab-B is intended to prepare and condition patients for a bone marrow transplant, also referred to as a hematopoietic stem cell transplant, which is often considered the only potential cure for patients with certain blood-borne cancers and blood disorders.

In an interview with OncLive, Sergio A. Giralt, MD, chief of the Adult Bone Marrow Transplant Service and the Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center, commented on Iomab-B and its potential, “New preparative regimens may allow for elimination of cells that could be potentially resistant to current conditioning strategies, Giralt noted. “Adding targeted agents to the pre-transplant conditioning regimen has the potential to increase the antitumor effect. Options include gemtuzumab ozogamicin, an anti-CD33 monocloncal antibody; Iomab-B (BC8-I-131 construct), a radiolabeled antibody-drug conjugate (via the monoclonal antibody BC8) targeted against CD45; and rituximab, an antibody directed against CD20,” he concluded.

On February 7th Actinium Pharmaceuticals announced that a Phase I clinical trial studying Actimab-M in multiple myeloma has been initiated. Actimab-M is comprised of the CD-33 targeting monoclonal antibody HuM-195 coupled to the alpha-particle emitter actinium 225. CD33 is an antigen found on hematopoietic cells in certain blood cancers. It is commonly associated with myeloid malignancies including AML, but recent research has shown that CD33 can also be found on malignant cells of approximately 25%-35% of all multiple myeloma patients. The expression of this marker increases in relapsed and refractory myeloma.

Trial collaboration with the National Cancer Institute
Agenus, an immuno-oncology company with a pipeline of immune checkpoint antibodies and cancer vaccines, announced recently a clinical trial collaboration with the National Cancer Institute (NCI). The double-blind, randomized controlled Phase II trial will evaluate the effect of of the company’s personalized autologous vaccine candidate, Prophage™ (HSPPC-96), in conjunction with Merck’s pembrolizumab on the overall survival rate of patients with newly diagnosed glioblastoma (ndGBM). The trial will be conducted by the Brain Tumor Trials Collaborative (BTTC), a consortium of top academic centers led by Mark Gilbert M.D. of the Neuro-Oncology Branch at the NCI Center for Cancer Research.

This month, Exelixis and Takeda Pharmaceutical Company announced an exclusive licensing agreement for the commercialization and further clinical development in Japan of cabozantinib, Exelixis’ lead oncology medicine. With the signing of the agreement, Takeda gains exclusive commercial rights for all potential future cabozantinib indications in Japan.

“As an organization with a strong focus on oncology innovation, our agreement with Exelixis brings a promising and well-studied solid-tumor therapy to our pipeline that may help patients in Japan suffering from RCC and potentially other equally devastating cancers,” noted Tsudoi Miyoshi, Head of Japan Oncology Business Unit of Takeda.

Columbus trial
In November 2016 Array BioPharma and Pierre Fabre jointly announced the new results from the pivotal Phase III COLUMBUS trial of binimetinib plus encorafenib (bini/enco) treatment in BRAF-mutant melanoma patients at the Society for Melanoma Research Annual Congress. The study met its primary endpoint, with the combination of bini/enco significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone. Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and over 10,000 deaths from the disease expected in 2016.

Olaparib
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly growing portfolio of new medicines that have the potential to transform patients’ lives. The company recently announced positive results from its Phase III OLYMPIAD trial comparing olaparib (Lynparza) tablets (300 mg twice daily) to physician’s choice of a standard of care chemotherapy in the treatment of patients with HER2-negative metastatic breast cancer harbouring germline BRCA1 or BRCA2 mutations. Patients treated with olaparib showed a statistically-significant and clinically-meaningful improvement in progression-free survival or PFS compared with those who received chemotherapy.

But AstraZeneca, who bought Spirogen in 2013, is, through its biologics unit MedImmune, also heavily involved with the development novel antibody-drug conjugates. Spirogen has developed a potent and flexible class of ADC payloads based on the company proprietary Pyrrolobenzodiazepine (PBD) technology, which are now included in the AstraZeneca/MedImmune pipeline.

However, the company’s oncology pipeline also includes other antibody-drug conjugates, including the anti-HER2 antibody-drug conjugate MEDI4276, an antibody-drug conjugate composed of a bispecific antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2; ERBB2). This investigational drug links an anti-HER2 antibody via a cleavable linker, to the cytotoxic anti-microtubule agent tubulysin, with potential antineoplastic activity.

With a robust oncology pipeline of investigational therapies in varied stages of clinical development, the company strives to eliminate cancer as a major cause of death.


Last Editorial Review: March 2, 2017

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Phase I Trial of SGN-CD352A in Relapsed or Refractory Multiple Myeloma Initiated

This week the first patient enrolled in a multi-center phase I clinical trial of SGN-CD352A for the treatment of patients with relapsed or refractory (r/r) multiple myeloma. SGN-CD352A is an investigational CD352-targeted antibody-drug conjugate (ADC) utilizing Seattle Genetics’ proprietary ADC technology, an engineered cysteine antibody (EC-mAb) stably linked to a highly potent cytotoxic agent called a pyrrolobenzodiazepine (PBD) dimer. [1]

Antibody-drug conjugates are designed to selectively deliver cell-killing agents to tumor cells, and thus may reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

CD352 is broadly expressed on B-cell cancers including multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, while exhibiting low expression on normal white blood cells. The CD352 engineered cysteine antibody is stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine dimer via site-specific conjugation technology (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the EC-mAb technology allows uniform drug-loading onto an ADC. The ADC is designed to be stable in the bloodstream and to release its potent cell-killing PBD agent upon internalization into CD352-expressing cells.

Multiple Myeloma
Multiple myeloma is a rare and aggressive cancer that forms in white blood cells called plasma cells. Normal, healthy, plasma cells are found in the bone marrow are an important part of the immune system. In contrast, malignant or cancerous plasma cells, which can crowd out healthy blood cells, impair bone strength and weaken the immune system.[2]

The immune system is made up of several types of cells that work together to fight infections and other diseases. Lymphocytes are the main cell type of the immune system – major types of lymphocytes are both T cells and B cells.

Despite recent medical advances, the disease remains an incurable disease in which patients eventually progress and die. Within one year of first-line therapy, 32% of transplant patients and 44% of non-transplant patients relapse. Remission periods are typically shorter for each subsequent line of therapy, with some patients receiving more than four lines of treatment over the course of their disease. After lymphoma and leukemia, multiple myeloma is the third most common blood cancer in the US. According to the World Health Organization, in 2015 more than 124,000 new cases of multiple myeloma were diagnosed worldwide and more than 87,000 people died from the disease. [3]

Trial design
The new clinical trial (NCT02954796) is designed to assess the safety and antitumor activity of SGN-CD352A. This study represents Seattle Genetics’ first clinical-stage ADC program in development for multiple myeloma, demonstrating the breadth of potential therapeutic applications for its industry-leading ADC technology platform.

“More than 124,000 people worldwide are diagnosed annually with multiple myeloma, most relapsing or becoming resistant to current therapies,” noted Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics.

“SGN-CD352A is a novel targeted investigational compound for multiple myeloma, and it is our latest antibody-drug conjugate, or ADC, in an expanding and robust pipeline of clinical stage empowered antibody therapies to address blood cancers and solid tumors. As we begin clinical development of our first compound for multiple myeloma, we continue to explore the broad potential of our ADC technology platform for people with cancer,” Lechleider concluded.


“More than 124,000 people worldwide are diagnosed annually with multiple myeloma, most relapsing or becoming resistant to current therapies”


The phase I, open-label multicenter clinical study is designed to evaluate the safety and preliminary antitumor activity of SGN-CD352A as a single agent in adults with relapsed or refractory multiple myeloma. The trial will be conducted in two parts, with a dose escalation part to identify the maximum tolerated dose of SGN-CD352A followed by an expansion part to further define safety and antitumor activity. SGN-CD352A will be administered every four weeks, and the study will enroll approximately 75 relapsed or refractory patients at multiple centers in the United States.

AACR 2016
Preclinical SGN-CD352A data presented at the 2016 American Association of Cancer Research (AACR) Annual Meeting demonstrated that SGN-CD352A specifically binds to target cells and induces potent antitumor activity in both multiple myeloma and non-Hodgkin lymphoma disease models. In addition to being a potential new monotherapy for multiple myeloma, the tolerability profile from preclinical results suggests that SGN-CD352A may be combined with current standard of care treatments for multiple myeloma.


Last Editorial Review: January 5, 2017

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Cancer Research Technology, University of Copenhagen and ADC Therapeutics Sign Agreement

Cancer Research Technology UK and the University of Copenhagen announced their agreement with Switzerland-based ADC-Therapeutics SA  to develop novel antibody therapeutics for the treatment of cancer.

The University of Copenhagen agreed with ADC Therapeutics to license antibodies against a cancer-specific cell surface protein. The antibodies will be used by ADC-Therapeutics to develop a novel antibody-drug conjugate or ADC that could potentially treat a range of cancers.

The antibodies – jointly developed by scientists from Cancer Research UK and the University of Copenhagen – target a protein overexpressed on the surface of some cancer cells, which is not expressed on healthy cells.

ADC-Therapeutics intends to incorporate the antibodies into a novel antibody-drug conjugate using its proprietary linker and pyrrolobenzodiazepine (PBD) cytotoxic warhead technology. The antibodies are expected to selectively target the PBD cytotoxic to cancer cells, sparing normal tissue. [1]

Pyrrolobenzodiazepines are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. They are significantly more potent than systemic chemotherapeutic drugs. Novel results demonstrate that PBDs can be effectively used for antibody-targeted therapy.[1]

New cancer treatments
“We are very pleased and proud that research from the University’s Faculty of Health and Medical Sciences has been licensed to ADC-Therapeutics for the development of new cancer therapeutics,” noted Thomas Bjørnholm, Pro-Vice-chancellor for Research and Innovation, the University of Copenhagen.

“Our mission as a public university is precisely to make sure that our leading-edge research is disseminated and is taken to the market together with commercial partners for the benefit of society at large,” Bjørnholm continued.

“This important license deal brings together CRT’s access to world class research and ADCT’s cutting edge technology to develop exciting new therapeutics for cancer,” added Keith Blundy, Ph.D, Cancer Research Technology’s chief executive.

“We hope this agreement will pave the way for promising new ways to treat a range of cancers in a targeted way without damaging healthy tissue,” Blundy concluded.


Last Editorial Review: April 23, 2016

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Regeneron and MedImmune Sign Licensing Agreement for Pyrrolobenzodiazepine-based Payload and Linker Technology

This month Regeneron Pharmaceuticals, a science-based biopharmaceutical company based in Tarrytown, New York and MedImmune, the global biologics research and development arm of AstraZeneca  entered into a licensing agreement under which Regeneron will use MedImmune’s pyrrolobenzodiazepine (PBD)-based payload and linker technology to produce antibody-drug conjugates (ADCs) as potential, novel, cancer treatments.

ADCs are a promising area of cancer drug technology which may help enable the selective killing of cancer cells by combining a cytotoxic agent, sometimes referred to as a “warhead” or “payload,” with specific cancer-targeting monoclonal antibodies.

The pyrrolobenzodiazepine (PBDs) – used as “payload,” are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. They are significantly more potent than systemic chemotherapeutic drugs.

In vitro, pyrrolobenzodiazepines typically demonstrate IC50 values in the low to mid picomolar range in a variety of cell types, and unlike the anti-tubulin agents, they can induce cell death in both dividing and non-dividing cells. Fully synthetic PBD dimers are ideally suited for the role of payload in an antibody-drug conjugate because, unlike other cytotoxic payloads such as calicheamycin, they combine potency with a demonstrated therapeutic index, are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders such as maytansinoids and auristatins that currently dominate the antibody-drug conjugate arena.

The pyrrolobenzodiazepine (PBD) dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. Pyrrolobenzodiazepine dimers have been shown to have broad spectrum anti-tumour activity in vivo. These novel drugs exert their activity by binding in the minor groove of DNA and linking the two DNA strands together in a way that cells find difficult to recognise and repair.

The technology was originally invented and developed by Spirogen, a company acquired by MedImmune in 2013.

Exclusive rights
The two companies agreed that Regeneron will have exclusive rights to utilize MedImmune’s proprietary PBD technology to develop ADCs against a number of cancer targets, while MedImmune will have the option to develop and commercialize certain products created with this technology in territories outside of the United States.

Key strategy
“Developing next generation antibody-drug conjugates, including our proprietary PBD technology, is one of our key strategic platforms in advancing cancer therapies. Today’s collaboration represents our third partnership in this area, as we look to grow our ADC portfolio both internally and externally,” noted Ronald Herbst, Vice President, Oncology Research & Development, MedImmune. “We are pleased to be working with Regeneron, a company that is committed to advancing scientific innovation in cancer treatments. Regeneron’s research capabilities complements our commitment to discovering and developing the next generation of cancer therapies.”

Multiple innovative therapies and technologies
“We believe the most successful approaches to cancer R&D will combine multiple innovative therapies and technologies, and therefore we are pursuing a diverse array of strategies, pathways and modalities including ADCs, bispecific antibodies and monocolonal antibodies,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. “This new agreement will further bolster our efforts to advance new, effective treatment options for cancer patients in need.”

Clinical pipeline
Regeneron’s clinical pipeline in oncology includes a PD-1 checkpoint inhibitor antibody, which is being developed in collaboration with Sanofi, and a CD20xCD3 bispecific. MedImmune is committed to advancing its pre-clinical and clinical stage ADC portfolio, in addition to its focus in immune-oncology, a strategy which rests upon the concept that the body’s own immune system can be unleashed or re-engaged to attack, eliminate or control cancer.

As part of the agreement, MedImmune will receive an upfront royalties on net sales of such products. Regeneron expects to advance multiple additional candidates into human clinical trials over the next 12 to 24 months.


Last Editorial Review: April 7, 2016

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Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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