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.
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.  Scientists have also confirmed the preponderance of CD25+ cells in hematological malignancies (malignant lymphomas including B-cell malignancies)  and the relationship between increased CD25 expression and poor prognosis  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).
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.
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.
 Study of ADCT-301 in Patients With Selected Advanced Solid Tumors – NCT03621982
 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.
 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.
 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.
 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.
A study published in the March 2018 edition of Molecular Cancer Therapeutics shows that, while antibody–drug conjugates or ADC have become important scaffolds for targeted cancer therapies, ADC exposure–response correlation is not well characterized.
Donglu Zhang, Shang-Fan Yu, Cyrus Khojasteh and their other colleagues at Genentech have demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs, bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer or PBD, in HER2-expressing xenograft models.
The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an antibody-drug conjugate can deliver an excessive level of payload to tumors that does not enhance efficacy – which may be referred to a the “Plateau” effect.
In contrast to tumor PBD concentrations, related assessments of systemic exposures, plasma stability, and drug-to-antibody ratio or DAR changes of related ADCs did not consistently rationalize the observed ADC efficacies.
Minimal efficacious dose
A minimal efficacious dose could be determined by ADC dose-fractionation studies in the xenograft models. Mechanistic investigations revealed that both linker immolation and linker disulfide stability are the key factors that determine intratumor PBD concentrations.
The results of the study clearly demonstrates how a linker design can impact ADC efficacy and that the intratumor exposure of a payload drug as the molecular mechanism quantitatively correlate with and predict the antitumor efficacy of antibody-drug conjugates.
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.
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.
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 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.
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. 
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.
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.
A new Phase I/II clinical program in which Bristol-Myers Squibb collaborates with AbbVie will evaluate the safety, tolerability and efficacy of the investigational biomarker-specific antibody-drug conjugaterovalpituzumab tesirine, also known as Rova-T (SC16LD6.5; Stemcentrx/AbbVie), in combination with nivolumab (Opdivo; Bristol-Myers Squibb), designed to alleviate immune suppression as a treatment for relapsed extensive-stage small cell lung cancer (SCLC).
The new study, expected to start patient enrollment later this year, will determine if the targeted cell killing and antigen release caused by rovalpituzumab tesirine may further enhance the effect of immunotherapy and evaluate if it drives improved and sustained efficacy and tolerability above the current standard of care.
Rovalpituzumab tesirine, is a novel, investigational, antibody drug conjugate developed by Stemcentrix that targets and eliminates tumor initiating cells and other bulk tumor cells. The drug targets the cancer-stem cell-associated target delta-like protein 3 (DLL3) which is expressed in more than 80% of small cell lung cancer (SCLC) patient tumors, where it is prevalent on tumor cells, including cancer stem cells, but not present in healthy tissue.
Minimizing toxicity to healthy cells
As an antibody-drug conjugate, rovalpituzumab tesirine is comprised of the D6.5 Pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2.  Since the drug delivers a cytotoxic agent directly to the DLL3-expressing cancer cells it minimizing toxicity to healthy cells. 
Based on the agreement between the two companies, AbbVie will initiate a first-line clinical study for rovalpituzumab tesirine in SCLC and several other types of tumors in the near term.
The investigational agent, is currently is under investigation as a third-line treatment in SCLC. Studies evaluating rovalpituzumab tesirine as a first-line SCLC regimen will be starting in the near term. The expression of DLL3 suggests rovalpituzumab tesirine may be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme and some prostate, pancreatic and colorectal cancers.
The trial evaluates rovalpituzumab tesirine in combination with nivolumab the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 54 countries including the United States, Japan, and in the European Union as a single agent for the treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma.
The drug is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy and for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin.
In the United States these indication are approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
In order to survive, cancer cells may exploit ‘regulatory’ pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Nivolumab, a PD-1 immune checkpoint inhibitor, binds to the checkpoint receptor PD-1 expressed on activated T-cells and blocks the binding of PD-L1 and PD-L2. This in turn, prevents the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.
A targeted approach
“We are excited to explore the potential benefits of combining Bristol-Myers Squibb’s immunotherapies with a targeted approach like Rova-T in small cell lung cancer where the need for new therapies is particularly acute for this aggressive form of lung cancer,” said Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb.
“As the science around cancer research continues to rapidly evolve, we are building on our leadership in Immuno-Oncology with numerous collaborations that may help advance new therapies for cancers in need of better options,” Valett added.
Priming the immune system
“We believe the combination of these cancer-fighting agents may offer patients a new treatment option in a disease with limited therapies,” said Scott J. Dylla, Ph.D., vice president, research and development, AbbVie. “By combining immune-checkpoint inhibitors that prime the body’s immune system to fight cancer cells with Rova-T’s approach to target cancer stem cells, we hope to build on our goal to develop differentiated treatments with therapeutic benefit that elevate the standard of care for small cell lung cancer patients.”
Difficult to treat
High-grade pulmonary neuroendocrine tumors, which include Small Cell Lung Cancer is a difficult-to-treat form of cancer that accounts for approximately 15% of all lung cancers. SCLC is an aggressive disease that is commonly metastatic at the time of diagnosis and is rarely amenable to surgery.  The disease predominantly develops in older patients with a history of smoking. The five-year survival rate for extensive-stage SCLC is less than 5% and treatment options are limited for the more than 234,000 people diagnosed annually. Because novel treatment options have not emerged for more than 30 years, SCLC belongs to the most deadly malignancies known. The current standard of care is chemotherapy with etoposide (Toposar™; Pfizer ) , a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases, and a platinating agent such as cisplatin (Platinol/Platinol AQ® ;Bristol-Myers Squibb) or carboplatin (Paraplatin® ;Bristol-Myers Squibb). 
The combined clinical trials fits in the Bristol-Myers Squibb vision for the future of cancer care that is focused on immuno-oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.
The company’s ongoing immuno-oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering clinical trials for overall survival and other important measures like durability of response. Hence, the collaboration with academia, as well as small and large biotech and pharmaceutical companies, to research the potential of immuno-oncology and non-immuno-oncology combinations is designed to investigate new treatment options in clinical practice.
Only a few weeks until the start of the 2016 annual meeting of the American Society of Clinical Oncology (ASCO). This year’s ASCO, taking place in the McCormick Place convention center in Chicago, Illinois, June 3-7, is expected to attract as many as 30,000 oncology professionals from the United States and around the world.
The theme of the annual meeting is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. The theme is noticeable throughout the entire annual meeting and reinforces the inextricable link – a necessity – between ongoing research and advances in patient-centered care. The 2016 theme is also evident as the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry, will be presented.
In preparation of the meeting, the program coordinators have accepted more than 5,200 abstracts to the ASCO Annual Meeting. Additional Late-Breaking Abstracts (LBAs), including Plenary abstracts, will be released on-site throughout the Annual Meeting.
Quality and access to care
Improving quality as well as access to appropriate care is a key subject being discussed during the 2016 annual meeting. Care may come in different forms, and researchers will discuss a phase III trial exploring whether using a mobile device-friendly web application for symptom monitoring improves survival of patients with lung cancer (Abstract LBA9006). Another study discusses a large analysis examining use of aggressive medical care and hospice for patients younger than age 65 in the last 30 days of life (Abstract LBA10033). Another study exploring racial disparities in receipt of breast and ovarian cancer risk-reducing procedures among younger breast cancer survivors with BRCA mutations (Abstract LBA1504). Cost of novel cancer therapeutics plays a role in access to these drugs. An analysis of cancer drug prices around the world (Abstract LBA6500) is expected to shine some light on the discrepancy in the availability of care.
One of the exciting development in the treatment of cancer includes immunotherapy. During the upcoming annual meeting, researchers will highlight studies representing the range of research topics, discuss survival data from early pre-clinical to phase III trials with a number of (novel) antibody-drug conjugates (ADCs) and other targeted therapies, include PD-1’s and BiTe’s.
Antibody-drug conjugates have, over the last decade, revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumor-associated target antigens and deliver a highly potent cytotoxic agent.
Today there are multiple ADCs in clinical trials, targeting varied antigens using different linker chemistries and cytotoxic payloads. In the development novel ADCs, scientists have met a number of challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA), how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel drugs may have the highest clinical benefit. 
Optimal target selection
The identification of optimal target is key to the clinical advancement of new antibody-drug conjugates. The possibilities of these novel targeted drugs used in the treatment of a wide range of solid cancers and hematological malignancies is limited by the discovery of suitable targets. Optimal targets are highly expressed on cancer cells and not, or minimally, on normal, healthy, tissues.
On Sunday morning, June 5, Howard A. Burris, MD (Sarah Cannon Research Institute) will be discussing the importance of the discovery of unique targets for antibody-drug conjugates designed to “make chemotherapy great again.”
Brentuximab vedotin Brentuximab vedotin (also known as SGN-035; Adcetris® by Seattle Genetics Inc.) is an antibody-drug conjugate (ADC) or immunoconjugate directed to CD30, which is expressed in classical hodgkin lymphoma and systemic anaplastic large cell lymphoma.
This year, as part of ASCO’s oral abstract session “Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia,” on Saturday June 4, Steven I. Park, MD (University of North Carolina Lineberger Comprehensive Cancer Center) will present data from phase II trial of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by brentuximab vedotin consolidation in limited stage non-bulky Hodgkin lymphoma (Abstract 7508).
During the poster discussion session on Monday, June 6, Anas Younes, MD (Memorial Sloan Kettering Cancer Center) will discuss results from Checkmate 205, a phase II study comparing safety and efficacy of nivolumab (Opdivo®; Bristol-Myers Squibb), a programmed death-1 (or PD-1) inhibitor approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of melanoma and advanced non-small cell lung cancer, in classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and brentuximab vedotin. (Abstract 7535, Poster Board: #91).
On Monday, Philippe Armand, MD, PhD (Dana-Farber Cancer Institute) will share an update of a phase I/II study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas. (Abstract TPS7576; Poster Board: #130a).
Another poster, presented by Somali C. Gavane, MBBS (Memorial Sloan Kettering Cancer Center) on Monday, includes an update of metabolic tumor volume to predict event-free survival in patients with relapsed/refractory Hodgkin lymphomas treated with brentuximab vedotin-based salvage therapy (Abstract 11566, Poster Board: #263).
Ado-trastuzumab emtansine, also know all T-DM1 (Kadcyla®; Genentech/Roche) is an antibody-drug conjugate consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC). The trastuzumab moiety binds to HER2 on tumor cell surface surfaces. Following internalization, the DM1 is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.
The linkage of antibody and drug through a nonreducible linker has shown to contribute to the improved efficacy and reduced toxicity of ado-trastuzumab emtansine compared to similar ADCs constructed with reducible linkers.
During the 2016 annual meeting, results from a large number of studies with ado-trastuzumab emtansine will be presented:
On Sunday, June 5, Carlos H. Barrios (PUCRS School of Medicine) will present a poster covering patient-reported outcomes from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab vs. trastuzumab + taxane for the treatment of HER2-positive advanced breast cancer (Abstract 593, Poster Board: #81);
The same day Audrey Mailliez, MD (Centre Oscar Lambert) will present response to ado-trastuzumab emtansine according to RANO criteria in central nervous system metastases of HER2 positive breast cancers (Abstract 605, Poster Board: #93);
Sunil S. Badve, MD (Indiana University) will present an update from the EMILIA trial discussing the role of tumor infiltrating lymphocytes (TILs) in HER2+ metastatic breast cancers (MBC) treated with ado-trastuzumab emtansine (T-DM1) or lapatinib plus capecitabine (Abstract 607, Poster Board: #95);
During the same poster session, Rachel A. Freedman, MD, MPH (Dana-Farber Cancer Institute) will present data about adjuvant ado-trastuzumab emtansine (T-DM1) for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. (Abstract TPS629, Poster Board: #109a).
Finally, Kathy Miller, MD (Indiana University Melvin and Bren Simon Cancer Center) will present results from the HERMIONE-trial, a phase II randomized, open label trial comparing MM-302 + trastuzumab with chemotherapy of physician’s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine. (Abstract TPS631, Poster Board: #110a)
During an oral abstract session on Monday, June 6 (breast cancer—HER2/ER), Sara A. Hurvitz (David Geffen School of Medicine, University of California Los Angeles) will discuss pathologic complete response (pCR) rates after neoadjuvant ado-trastuzumab emtansine + pertuzumab vs. docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (KRISTINE). (Abstract 500)
The anti-Trop-2-SN-38 antibody-drug conjugate (ADC) sacituzumab govitecan (IMMU-132), being developed by Immunomedics (Morris Plains, NJ 07950), is designed to deliver the moderately-toxic conventional chemotherapeutic drug, SN-38, the active metabolite of irinotecan (Camptosar®, Pfizer), site-specifically and at a high drug to antibody ratio (DAR), to a humanized antibody that targets the Trop-2 receptor, expressed by many solid cancers, while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.
During the clinical science symposium “Future directions in breast cancer treatment: new drugs, new markers,” on Friday, June 3, Aditya Bardia, MD, MPH (Massachusetts General Hospital Cancer Center) will present results from a phase II study of sacituzumab govitecan, for the treatment relapsed/refractory metastatic triple-negative breast cancer (mTNBC) (Abstract LBA509).
Results with the first-in-class antibody-drug conjugate sacituzumab govitecan in patients with previously treated metastatic small-cell lung cancer (mSCLC) will be presented in a poster session by Alexander Starodub, MD, PhD (Indiana University Health Goshen Center for Cancer Care) on Saturday, June 4, discussing “Lung Cancer—Non-Small Cell Local-Regional, Small Cell and Other Thoracic Cancers” (Abstract 8559; Poster Board: #187)
On Monday, June 6, during the clinical science symposium “Raising the bar for targeted therapies for lung cancers,” D. Ross Camidge, MD, PhD (University of Colorado), will present new approaches to the treatment of metastatic, non-small cell lung cancer (mNSCLC) with sacituzumab govitecan (Abstract 9011).
Rovalpituzumab tesirine combines a novel targeted drug (anti-DLL3 antibody) with a toxin, D6.5 pyrrolobenzodiazepine (PBD), which is conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. 
On Sunday, June 5, Charles M. Rudin, MD, PhD (Memorial Sloan Kettering Cancer Center) will present results from a phase I/II study investigating the safety and efficacy of antibody-drug conjugate rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, for the treatment of recurrent or refractory small cell lung cancer (SCLC) (Abstract LBA8505).
New indication of rovalpituzumab tesirine also include the potential treatment of metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs). Initial results are presented in a poster presentation on June 6 by Stemcentrx‘s Stanford L. Peng, MD, PhD will present (Abstract 11611, Poster Board: #308).
Prostrate-specific membrane antigen or PSMA is a protein that is highly expressed on most of the tumor cells in prostate cancer. The protein is also expressed on the (neo)vasculature that supplies blood to many other tumors. Researchers at Ambrx (La Jolla, CA 92037) have developed a site specific antibody-drug conjugate using the company’s proprietary drug payload. The trial drug, which is being evaluating for efficacy and overall toxicity compared with conventional antibody-drug conjugates, may have the potential to demonstrate increased potency in cancer patients while decreasing the toxicity that is usually seen in other antibody-drug conjugates due to the heterogeneity of the random conjugation approach used to generate these molecules. The anti-PSMA ADC is being developed for the treatment of patients with prostate cancer and glioblastoma multiforme.
On Saturday, June 4, Heinrich Elinzano, MD (Rhode Island Hospital) will present results of the Phase II Brown University Oncology Research Group Study investigation the novel PSMA ADC in patients with progressive glioblastoma (Abstract 2065; Poster Board: #252)
The potential treatment of glioblastoma (GBM), the most common malignant primary brain tumor, is also presented by Martin J. Van Den Bent, MD (Erasmus MC Cancer Center) in a poster presentation reviewing the efficacy of ABT-414 (AbbVie), composed of the antibody ABT-806 targeting active EGFR/mutant EGFRvIII linked to the anti-microtubule agent monomethyl auristatin F, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (Abstract 2542; Poster Board: #242).
Scientists have identified aberrant EGFR expression and signaling as a hallmark of cancer growth and survival. In several EGFR-overexpressing tumor xenografts ABT-414 has shown potent anti tumor activity.
The antibody-drug conjugates enfortumab vedotin comprises the human anti-nectin-4 antibody conjugated to the highly potent microtubule disrupting agent monomethyl auristatin E (MMAE). Scientists at Agensys (Santa Monica, CA, 90404) prepared hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME). They were able to bind the the versions of enfortumab vedotin to cell surface expressed nectin-4, a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules and reported high affinity and induced cell death in vitro in a dose-dependent manner. 
Using mouse xenograft models of human breast, bladder, pancreatic, and lung cancers, scientists found that treatment with enfortumab vedotin significantly inhibited the growth these tumor types. They also noted tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.
On Monday, June 6, during a poster session covering genitourinary (non-prostate) cancers, Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center) will present data of the anti-tumor activity, safety and pharmacokinetics of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients with metastatic urothelial cancer. (Abstract 4533, Poster Board: #156).
Inotuzumab ozogamicin is an investigational ADC comprised of a humanized IgG4 anti-CD22 antibody targeting CD22, a cell surface antigen expressed on approximately 90% of B-cell malignancies, covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazine or calichDMH, a derivative of gamma calicheamicin, a cytotoxic antibiotic produced by the bacterium Micromonospora echinospora, with potential antineoplastic activity.
When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is rapidly internalized, delivering the conjugated CalichDMH intracellularly. The CalichDMH moiety then binds to the minor groove of DNA in a sequence-specific manner, resulting in double-strand DNA breaks and apoptosis.
The trial drug originates from a collaboration between Pfizer and Celltech (now part of UCB).
During the poster session “Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant” on Monday, June 6, a total of 3 posters with trial updates covering inotuzumab ozogamicin will be presented:
Hagop M Kantarjian, MD (The University of Texas MD Anderson Cancer Center, Department of Leukemia) will present patient-reported outcomes from a global phase III randomized controlled trial of inotuzumab ozogamicin vs. standard care for relapsed/refractory (R/R) acute lymphoblastic leukemia or ALL. (Abstract 7027, Poster Board: #19);
Daniel J. DeAngelo, MD, PhD (Dana-Farber Cancer Institute) will present the efficacy and safety by prior therapy of inotuzumab ozogamicin for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia in the phase III INO-VATE trial.(Abstract 7028, Poster Board: #20), and
Elias Jabbour, MD (The University of Texas MD Anderson Cancer Center) will follow with data of the efficacy and safety of inotuzumab ozogamicin in older patients with relapsed/refractory acute lymphoblastic leukemia (ALL) who were enrolled in the phase III INO-VATE trial.(Abstract 7029,Poster Board: #21).
The presented results stem from the INO-VATE trial, is an open-label, randomized, Phase III study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The two primary endpoints in this trial are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life based on the EORTC’s Quality of Life Questionnaire.
A (poster) presentation by George R. Blumenschein, M.D., Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, presents the results of a phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine, also known asBAY 94-9343, being developed by Bayer HealthCare under an agreement with ImmunoGen, consists of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker (Abstract 2509; Poster Board: #209). 
Upon internalization, the DM4 moiety in anetumab ravtansine binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells. Mesothelin is overexpressed on all mesotheliomas as well as many ovarian and pancreatic cancers while minimally expressed on normal tissue. 
Results from a number of studies with antibody-drug conjugates presented during ASCO include:
Results from a phase I, open-label, dose-escalation and expansion study of ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors. (Abstract 2510; Poster Board: #210), presented by John H. Strickler, MD (Duke University Medical Center)
A poster presentation by Carlos Alberto Gomez-Roca, MD (Institut Universitaire du Cancer de Toulouse) detailing the results of a phase I study of SAR566658, an anti CA6-antibody-drug conjugate created by ImmunoGen and licensed preclinically to Sanofi, in patients with CA6-positive advanced solid tumors (STs)(NCT01156870). SAR566658 comprises of ImmunoGen’s huDS6 CA6-targeting antibody conjugated to DM4 via one of the compansy’s engineered linkers (SPDB). (Abstract 2511; Poster Board: #211)
Results from mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer patients will be presented by Kathleen N. Moore, MD (University of Oklahoma Health Sciences Center) (Abstract 5567; Poster Board: #390)
Data from a randomized, open-label, phase II study of the anti-NaPi2b antibody-drug conjugate Lifastuzumab (Lifa) Vedotin, also known as DNIB0600A and RG-7599, being developed by Genentech/Roche, compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, will be presented by Susana N. Banerjee, MBBS, MA, PhD, MRCP (Royal Marsden Hospital). (Abstract 5569; Poster Board: #392).
Nanotechnology is a multidisciplinary field opening the door to a new generation of devices for cancer diagnosis, treatment and prevention. Drug-loaded nanoparticles offer considerable potential to provide a potentially ideal solution to solve some of the problems seen with traditional chemotherapy.
Although nanoparticles can become concentrated preferentially to tumors by virtue of the enhanced permeability and retention (EPR) effect of the vasculature, the low selectivity of nanoparticles towards the cancer cells hinders the advantages of the nanoparticle formulation for efficient chemotherapy. One reason is that a therapeutic agents such as docetaxel, a commercially successful oncology drug that suffers from a poor safety profile limiting its clinical utility, also kills healthy cells. To solve this problem, scientist have been working on the development of novel drugs containing docetaxel.
CRLX301 is a novel nanoparticle-drug conjugate (NDC) containing a docetaxel payload being developed by Cerulean Pharma (Waltham, MA 02451) for the treatment of patients with refractory solid tumors. The trial drug is expected to be differentiated from standard docetaxel because it is designed to concentrate more docetaxel in tumor cells and spare healthy tissue. Preclinical data show that CRLX301 had lower toxicity than has been reported with docetaxel in preclinical studies.
Ben Markman, MBBS, FRACP (Monash Cancer Center) will presents phase I trial results of CRLX301. (Abstract 2526; Poster Board: #226).
It’s just a few more weeks until the start of the 2016 annual meeting of American Society of Clinical Oncology. To help attendees plan their meeting, ASCO has developed a a new scheduling tool – the iPlanner – to browse abstract titles, search for sessions, or create a customized schedule. In addition, the organizers have developed a new ‘Insiders Guide‘ designed to help meeting attendees navigate the ASCO and make the best of their time during the 2016 annual meeting.
Every year, in addition to offering a forum to share clinical updates in all areas of oncology, ASCO offers it’s audience a valuable opportunity to actively participate in discussions with colleagues, conforming it’s standing among the leading oncology meetings around the globe.
Last Editorial Review: May 7, 2016 Last Editorial update: May 8, 2016
Late last week, Swiss based ADC Therapeutics, an oncology drug development company that specializes in the development of proprietary antibody-drug conjugates (ADCs) targeting major solid and hematological cancers, confirmed that the first patient has been dosed in a Phase I trial to evaluate its antibody-drug conjugate (ADC) ADCT-402 in B-cell non-Hodgkin Lymphoma (B-NHL).
The two stage, open-label trial will evaluate the tolerability, safety, pharmacokinetics and activity of ADCT-402 in patients with relapsed or refractory B-NHL. The first stage is a dose escalation phase which will recruit up to 30 patients at ten clinical sites across the US and EU and will seek to determine the recommended dose of ADCT-402 for the second stage. The second stage, which will begin once an appropriate dose is identified, aims to confirm the safety and efficacy profile at the selected dose.
ADCT-402 combines a humanized monoclonal antibody targeting the protein CD19 with a pyrrolobenzodiazepine (PBD) payload. CD19 is a B-cell specific surface protein expressed throughout B-cell development. It is expressed on nearly all B-cell malignancies in many non-Hodgkin lymphomas. Due to its specificity, it has become an attractive target for ADC therapies. In preclinical in vivo models, ADCT-402 exhibited strong dose-dependent anti-tumor activity against CD19-positive leukemic and lymphoma cell lines at low single doses, and it outperformed other CD19 targeted ADCs currently in clinical development.
B-cell non-Hodgkin Lymphoma is a common type of non-Hodgkin lymphoma, a cancer of the lymphatic system. Non-Hodgkin Lymphomas overall are the 10th most common cancer in the world. In 2012, there were nearly 386,000 new cases diagnosed globally, with highest incidence rates reported in Northern America.
“Dosing the first patient in this trial with ADCT-402 is an important milestone for us and could pave the way for a better treatment regimen for patients. The trial will give us vital data on safety, tolerability, dosing and efficacy over the next two years,” noted Jay Feingold, MD, the Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.
“Following our preclinical studies suggesting ADCT-402 may also provide significant clinical benefit for patients suffering from lymphoblastic leukemia, we are exploring this potential further with a second study in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia now also open for patient recruitment,” Feingold continued.
“Tremendous advances have been made in the treatment of non-Hodgkin Lymphoma in the past 20 years. However, a significant portion of the patient population still fail to respond to currently available therapies. Having seen the effects of other ADCs in various tumour types in recent years, we eagerly anticipate the results of this study,” explained Owen O’Connor, MD, Principal Investigator for the study and Professor of Medicine and Experimental Therapeutics, and the Director of the Center for Lymphoid Malignancies at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center,
ADC Therapeutics currently has two PBD-based ADCs in four clinical trials, with a deep pipeline of other ADCs in preclinical development. The company’s ADCT-301 and ADCT-402 programs entered Phase I clinical development for lymphoma and leukemia in 2015.
Currently, there are more than 30 antibody drug conjugates or ADCs in clinical trials, with many more expected in the near future. ADCs are expected to revolutionize the way cancer is treated, and advancements in engineering and research are making this goal all the more attainable than ever before. At the 2016 Cambridge Healthcare Institute’s PepTalk, the Protein Engineering Week, held January 18 – 22, 2016 in San Diego, CA, scientists and researchers participated in the 3rd Annual Antibody-drug Conjugate conference ‘pipeline’, note first hand how engineering that has brought about today’s revolution is paving the way for next generation safe and effective ADCs.
The conference also highlighted strategies for advancing ADCs to the clinic as well as considerations for clinical trial design as well as analyzing ADCs to explore conjugation, stability, payloads and tumor penetration.
Peter Senter, Ph.D., the Vice President of Chemistry at Seattle Genetics, in the keynote presentation, reviewed the history of successes and challenges seen with ADCs, and discussed future innovations to enhance efficacy and reduce toxicity. Brentuximab Vedotin (Adcentris®; Seattle Genetics), one of the two current FDA-approved ADCs, was included as an example of past and present successes as well future development prospects for use in front line therapy.
Brentuximab vedotin has had remarkable results in treating patients with refractory or relapsed classic Hodgkin’s Lymphoma. Patients treated with brentuximab have continued to be followed for four years, and are reaching an impressive median overall survival or MOS of 3.4 years, compared to the typical MOS of just over a year usually seen in these patients. Additionally, a MOS is yet to be reached in patient groups with anaplastic large cell lymphoma even after four years, which is a significant success when considering that this patient group, when disease is refractory, has historically had an MOS of only six months.
The success of brentuximab has led to its investigation as front-line therapy, where researchers at Seattle Genetics are hoping to reach their goal of eventually replacing cytotoxic chemotherapies with slect ADCs altogether.
In this Phase III trial, patients were given ABVD, the traditional treatment combination of four chemotherapeutic drugs used tomtreat Hodgekin lymphoma. It includes the drugs doxorubicin hydrochloride (Adriamycin), bleomycin sulfate, vinblastine sulfate, and dacarbazine. While the combination, along with brentuximab showed a nearly complete rsponse rate (70-80%), pulmonary toxicity was very high. Since it was predicated that bleomycin sulfate, the “B” in ABVD, may have caused this toxicity. Because researchers believed that this toxicity was somehow enhanced by brentuximab, bleomycin,was taken out of the ABVD combination. Reviewing the data, the researchers observed the same response rate without pulmonary toxicity. 
In discussing future ADC approaches, Senter, amongst many others at the conference, showed that a thorough understanding of the cause of toxicities is truly key for advancement. And for many ADCs in clinical trials, as well as for brentuximab, there are non-target toxicities that are commonly seen to be independent of the target or cancer being investigated. Therefore, much of the research for future ADCs is focused on improving drug potency while reducing adverse effects.
Various presentations further addressed the issue of improving toxicity.
Because therapeutic index is a major hurdle in developing novel Antibody-drug Conjugates, there is considerable effort to understand the relationship between the properties of ASDCs and safety in order to engineer second generation ADCs with better therapeutic index.
Mary J. Hinrichs, Ph.D., the Principal Toxicologist for Biological Safety Assessment at MedImmune, discussed the translatability of traditional nonclinical safety studies to clinical toxicity, as well as the importance of pre-clinical studies in terms of determining drug safety, how using non-traditional screening strategies may help in developing the best ADC constructs and the relationship between normal tissue expression and on/off target toxicity, as well as engineering factors that impact safety of Antibody-drug Conjugates.
While there are difficulties in seeing if toxicity predictions are correct from autonomised data such as was presented Hinrichs, correlations can still be seen from preclinical studies. Furthering this data can potentially improve the chances of developing a successful ADC. In fact, Hinrichs noted that a recent publication from the U.S. Food and Drug Administration (FDA) showed that within 11 different IMDs, major toxicities were able to be determined for each one. The publication confirmed that when rank ordered based on incidence, the leading toxicities were in line with what you would expect with a cytotoxic agent. Additionally, when these were compared to the major dose limiting toxicities of 16 different Antibody-drug Conjugates, myelosuppression was identified as number one in both cases, and others such as liver and gastrointestinal toxicities were also successfully identified pre-clinically.
“As a field as a whole, it’s clear that the major toxicities are being evaluated preclinically,” stated Hinrichs “What we don’t know is if this will relationship hold true for other ADCs employing novel types of warheads.”
Hinrichs also discussed how a correlation between toxicities found in a pre-clinical setting and those observed in clinical trials can help in the advancement of ADCs especially with highly potent payloads. Currently, many researchers strive to achieve constructs with higher potency, but are limited by the negative correlation between drug safety and potency, leading to very narrow range for therapeutic index. For this reason, researchers at Immunogen are creating improved strategies for considering all factors that may affect chances of success. An example of this presented was a study to investigate how normal tissue expression can impact the safely profile of a high toxic
Pyrrolobenzodiazepine (PBD) ADC.
PBD ADCs work by cross-linking DNA in order to kill both rapidly dividing tumor cells and slowly dividing tumor stem cells. In the study, two PBD ADCs that only differed in their complementary determining region (CDR) were compared. One PBD targeted a tumor antigen that was seen to high expression on tumors and low expression on normal tissue, while the other was non-targeted. When compared in monkeys, the non-targeted ADC was able to be dosed as high as 1mg/kg and showed only mild injection site skin reactions. This was a very different response than observed with the targeted PBD test, in which the monkeys had to be put down after 21 days because of severe skin toxicities.
“This is a good example of how low level normal tissue expression can increase the potential for non-target toxicity,” Hinrichs noted. “But it’s not always easy to predict it before you go in vivo,” she continued. 
While advancements in linker chemistries and conjugation technologies have helped in improving the therapeutic index, there are a lot of relationships that are not yet fully understood. There is a great need to identify the best possible constructs with the best safely profile. This has led Immunogen to develop a safely screening plan in order to identify these best possible ADCs to move forward. This strategy includes the use of rat model that can provide more research possibilities vs. using only non-human primates, including evaluating the impact of engineering changes, screening for novel warheads, and looking for relationships between efficiency and safely before continuing with an ADC.
“There are still a lot of questions left for highly potent payloads,” Hinrichs explained.“It is really important to change the strategy that we use to access the chances of a molecule having clinical success.”
And while it is clear that challenges still remain in ADC development, knowledge of the relationship between drug potency and toxicity is continuously being expanded. Improved technologies and pre-clinical strategies are certainly expected to pave the way for promising next-generation Antibody-drug Conjugates.
Last Editorial Review: February 15, 2016 Last Editorial update: March 16, 2016
ADC Therapeutics, an oncology drug discovery and development company headquartered in Lausanne, Switzerland and London, UK, that specializes in the development of proprietary Antibody Drug Conjugates (ADCs) targeting major cancers, has raised $80 million through a private placement of equity. New investors include leading European and US-based investors alongside founding investor Auven Therapeutics and participation from AstraZeneca.
The proceeds will be used to progress ADC Therapeutics’ product portfolio. The development pipeline includes the company’s lead program, ADCT-301, for the treatment of relapsed/refractory Non-Hodgkin or Hodgkin lymphoma, which entered Phase I clinical trials (NCT02432235) earlier this year. The proceeds will also benefit the collaboration to develop up to two ADCs for commercialization with MedImmune, the global biologics research and development arm of AstraZeneca.
The antibody-drug conjugates being developed by ADC Therapeutics are highly targeted drug constructs which combine monoclonal antibodies (mAbs) specific to surface antigens on particular tumor cells with highly potent pyrrolobenzodiazepine (PBD)-based warheads. The company anticipates having seven drug candidates in human clinical trials in 2017.
ADCT-301, the company’s lead program, is an antibody-drug conjugate composed of a recombinant human IgG1, HuMax®-TAC against human CD25 attached to a PBD warhead. 
The Interleukin-2 receptor-α (IL2R-α, CD25) is one of a heterotrimer making up the IL2R. It plays a major role in signal transduction pathways involved in the pathogenesis of autoimmunity and graft rejection.  Based on the preponderance of CD25+ cells in hematological malignancies as well as the relationship between increased CD25 expression and poor prognosis, researchers became interested in investigating the possibility of using an anti-CD25 antibody to deliver a cytotoxin to these specific cells in patients. The clinical proof of concept for treatment of CD25-positive malignancies was established using radio-immunoconjugates and immunotoxins with antibodies basiliximab, a chimeric mouse-human monoclonal antibody to the α chain (CD25) of the IL-2 receptor of T cells, and the humanized monoclonal antibody daclizumab. 
During the 56th Annual Meeting of the American Society of Hematology (ASH) in December 2014, investigators reported that ADCT-301 demonstrated dose-dependent in vivo antitumor activity against SUDHL1 and Karpas 299 xenograft and disseminated models. The investigators showed that the trial drug, at a single dose of 0.2 mg/kg, significantly delayed Karpas 299 tumor growth compared to vehicle-treated and isotype control ADC-treated mice, and at 0.4 and 0.6 mg/kg gave 3/10 and 10/10 tumor-free survivors, respectively. 
The investigators also observed 10/10 tumor-free survivors at a single dose of 0.5 mg/kg. In contrast, treatment with brentuximab vedotin (Adcetris®, Seattle Genetics) only resulted in a modest delay in mean tumor growth at a single dose of 0.5 mg/kg despite this tumor expressing three times the level of the brentuximab vedotin target CD30 antigen compared to CD25. The investigators also reported that ADCT-301 was well tolerated with no signs of toxicity at 6 mg/kg, which was, at the time of the presentation, currently the highest dose tested. 
ADC Therapeutics was established in 2012 by private equity firm Auven Therapeutics. In 2013, MedImmune acquired an equity stake in the company and entered into a joint collaboration for two of the antibody-drig conjugates being developed by ADC Therapeutics.
To facilitate the development, ADC Therapeutics has built a highly experienced R&D team in the UK, as well as legal, finance and EU clinical teams in Switzerland, and regulatory, clinical and manufacturing teams in the US. The company also works closely with a number of specialist partners in Europe and the US for regulatory, clinical trial management and manufacturing activities.
In June, Chris Martin, PhD, a co-founder of Spirogen Ltd and its Chief Executive Officer leading up to the sale of Spirogen to MedImmune and a recognized leader in the ADC space, joined ADC Therapeutics as Chief Executive Officer, after having played a key role in the formation and strategy of the company as a member of its Board of Directors. Martin has also served as a member of MedImmune’s Leadership Team.
Commenting on securing the funding, Martin noted: “The significant advances we have made in progressing our pipeline of ADCs have been recognized by this financing round. In a major milestone for the company, our first ADC candidate drug entered the clinic earlier this year and we are on track to file for our second IND with the FDA by the end of October.”
“The quality of investors we have been able to attract and the size of this investment round, just over three years since the Company was founded, is a great endorsement of our strategy and potential. This financing provides the funds required to aggressively develop our pipeline of proprietary ADCs with best-in-class PBD-based warheads and linkers as an important part of the next-generation of cancer drugs, with the potential to impact cancer patients worldwide,” Peter B. Corr, MD, PhD, Chairman of the Board of ADC Therapeutics and co-founder and Managing General Partner of Auven Therapeutics, added.
The Company was advised by Christoph Ladanyi, co-founder and Managing Director of BLMS Capital, and its corporate legal counsel Homburger AG.
Last Editorial Review: September 2, 2015
Photo/Featured Image: Queen Mary Bioenterprises Innovation Center. Photo Courtesy: Queen Mary BioEnterprises Ltd , The QMB Innovation Centre 42 New Road, London E1 2AX.
Drug companies are aggressively pursuing the development of antibody-drug conjugates or ADCs, powerful three-part bioconjugates comprising a specific antibody targeting molecule, a highly potent cytotoxin payload inhibiting intracellular processes necessary for cell survival, and a linker to connect them. Antibody-drug conjugates are designed to specifically target various forms of cancer, while, at the same time, not harming healthy tissues. However, the current generation of antibody-drug conjugates offers limited benefits to patients because they are heterogeneous drug mixtures containing variants with sub-optimal pharmaceutical properties.
Earlier today, during a plenary session of the 2015 World ADC Summit, being held in the Marriott Marquis & Marina, October 26-29, 2014 in San Diego, California, Randall Halcomb, PhD, Vice President Chemistry at Igenica Biotherapeutics, presented new data utilizing the company’s SNAP site-specific ADC linker technology.
The proprietary linker technology addresses major limitations of current and competitive approaches by providing a simple, fast and robust chemically-driven methods for linking a functional, cancer targeting, antibody and small molecule cytotoxic drug to produce antibody-drug conjugates with optimal and uniform ratios of drug to antibody (DAR). The SNAP technology results in a highly flexible bi-functional linker that, by design, yields homogeneous antibody-drug conjugates armed with the optimal toxin payload.
Igenica has successfully applied this technology to synthesize antibody-drug conjugates using multiple antibodies and a variety of payloads.
At the World ADC Summit, Halcomb presented new data comparing the biophysical properties, in vitro potency, in vivo efficacy and pharmacokinetics of ADCs containing Igenica’s SNAP linkers compared to conventional ADCs. The presented findings validated the superiority of SNAP linkers in terms of uniformity, pharmacokinetics, stability and in vivo efficacy as compared to conventional antibody-drug conjugates.
SNAP linkers also enable improved process efficiency, including a fast, robust chemical conjugation and the ability to use traditional antibody production systems, in contrast to ADC approaches that require protein engineering.
Best Scientific Innovations
In addition, Igenica was recognized for its innovative SNAP technology as one of the finalist in the Best Scientific Innovation Category during the World ADC Awards ceremony, being held in conjunction with the World ADC Summit, on Sunday, October 26, 2014. This year, the winner of the category was Spirogen’s (part of AstraZeneca’s MedImmune) proprietary pyrrolobenzodiazepine (PBD) technology which attaches highly potent cytotoxic agents to specific cancer-targeting antibodies using biodegradable linkers. Other finalists in this category included Catalent Pharma Solutions‘ (Redwood Bioscience) SMARTag Technology, CytomX Therapeutics‘ Probodies, and Sutro Biopharma‘s cell free expression system.
“Igenica’s proprietary site-specific SNAP technology represents a breakthrough in ADC uniformity, process efficiency and drug product profile for the next-generation of homogeneous ADCs,” explained Mary Haak-Frendscho, Ph.D., Chief Executive Officer of Igenica. “Our innovative platform has the potential to produce drugs with lower toxicity and higher efficacy, representing an important benefit to cancer patients.”