This year, in Atlanta, the South’s largest and most vibrant city, the 59th annual meeting and exposition of the American Society of Hematology, to be held December 9-12, 2017, is expected to bring an invaluable educational experience and the opportunity to review thousands of scientific abstracts highlighting updates in the hottest topics in hematology.

The world’s most comprehensive hematology event of the year will provide an opportunity to Network with top minds in the field and a global community of more than 25,000 hematology professionals from every subspecialty.

New developments in antibody-drug conjugates are expected to create excitement.

Changing landscape
The landscape of antibody-drug conjugates is rapidly changing. [1]

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In January 2017 only two ADCs were commercially available in the United States.  This included brentuximab vedotin (Adcetris®; Seattle Genetics), an anti-CD30 monomethyl auristatin E (MMAE) conjugate indicated for the treatment of patients with relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, and ado-trastuzumab emtansine (also know as T-DM1; Kadcyla®; Genentech/Roche), an anti-HER2 DM1 conjugate used to treat HER2-metastatic breast cancer. a

For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual meeting of the American Society of Hematology, December 9 – 12, 2017, Click here.

Then in the late summer of this year the number of commercially available antibody-drug conjugates approved by the U.S. Food and Drug Administration (FDA) doubles with the approval, inotuzumab ozogamicin (Besponsa®; Pfizer) for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) and gemtuzumab ozogamicin (Mylotarg®; Pfizer) b, for relapsed/refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

With four commercially available antibody-drug conjugates, the majority of which are for the treatment of liquid cancers, and with a better understanding of cancer biology and many technological advances, this class of novel (anti-cancer) agents is finally beginning to deliver on decades old expectations and hope for better therapeutic outcomes.

But some of the hope and expectation are still ‘locked’ in early and preclinical research, as is evidenced by the fact there are more than 150 ADC and ADC-like agents in development programs.

Penelope Drake and David Rabuka, in a recent article published in BioDrugs, discuss how our better understanding and advances are based upon a large – and increasing – body of investigational studies which, taken together, offer a deeper knowledge and comprehension of the absorption, distribution, metabolism, and excretion (ADME), drug metabolism and pharmacokinetics (DMPK) fates of the intact conjugate and its small-molecule drug component.[1]

This year, during the annual meeting of the American Society of Hematology a number of  companies will again present their latest developments.

IMGN632 and IMGN779
ImmunoGen, will highlight two experimental ADC therapies, IMGN632 and IMGN779, a CD33-targeted ADC for the treatment of acute myeloid leukemia or Acute Myeloid Leukemia currently in Phase I testing.

Both IMGN779 and IMGN632 use ImmunoGen’s novel indolino-benzodiazepine payloads called IGNs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

Acute Myeloid Leukemia is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients are expected to die from the disease [2]

IMGN632 is a humanized anti-CD123 antibody-drug conjugate that is a potential treatment for for hematological malignancies, including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelodysplastic syndrome, B-cell acute lymphocytic leukemia, and other CD123-positive malignancies.

Earlier this year, ImmungGen announced that the Investigational New Drug application for IMGN632 is active and it expects to open a Phase I trial later this year.

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.

IMGN779 is in Phase I clinical testing for the treatment of AML.

“The clinical and preclinical data to be presented at ASH demonstrate the early potential of our novel IGN portfolio,” said Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

“One of our strategic priorities is to accelerate the development of these unique and highly differentiated assets. IMGN779 and IMGN632 use our IGN payloads, which were designed to meet the dual challenges of achieving high potency against target cells, while having a tolerability profile that enables continued patient treatment,” Gregory added.

In a poster presentation, the ImmunoGen is expected to report updated data evaluating the safety and anti-leukemia activity from the dose escalation phase of the IMGN779 first-in-human trial. In a separate presentation, preclinical data evaluating the mechanism, anti-leukemia efficacy, and tolerability of repeated dosing of IMGN779 and cytarabine in combination using in vitro and in vivo human AML preclinical models will be reported.

Preclinical data reporting the prevalence of CD123 expression in acute lymphoblastic leukemia (ALL), and assessing the anti-leukemia activity of IMGN632 on ALL cells will be presented in a poster presentation.

Novel payloads: Antibody-targeted Amanitin conjugates
Today, most antibody-drug conjugates, both commercially available and in clinical trials, includes just a limited number of cytotoxic payloads, generally limited to microtubuli- or DNA-targeting toxins including auristatins and maytansines or duocarmycins and pyrrolobenzodiazepines (PBDs). These payloads are mainly targeting proliferating cells potentially leading to limited efficacy in diseases with a low proliferation rates such as indolent lymphomas or multiple myeloma.

Researchers at the German Cancer Research Center, Heidelberg, Baden-Württemberg, Germany in collaboration with Heleidelberg Pharma are developing a novel antibody-drug conjugate with amanitin as toxic payload with an alternative toxicity mechanisms that could enhance the therapeutic potential of ADCs.

Amanitin is the most well-known toxin of the amatoxin family and binds to the eukaryotic RNA polymerase II, inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell.

During this year’s annual meeting, researchers from the German Cancer Research Center will present results of a study assessing in vitro and in vivo specificity and efficacy of HDP-101, an ATAC targeting BCMA (B cell maturation anti­gen; CD269), which is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. BCMA is highly expressed on malignant plasma cells and therefore considered an ideal target in multiple myeloma, is not expressed on naïve, germinal center, and memory B cells.

The researchers conclude that the mode of action of the amanitin payload led to an efficient anti-tumor response in vitro and in vivo with good tolerability in non-human primate studies yielding a very favorable therapeutic index.

A first-in-human trial with HDP-101 as a potential treatment for multiple myeloma is expected to start in 2018.

Brentuximab vedotin
This year 18 abstracts will featuring data from the broad brentuximab vedotin (Adcetris®; Seattle Genetics) development program. Brentuximab vedotin, an ADC directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, is being evaluated globally as the foundation of care for CD30-expressing lymphomas in more than 70 corporate- and investigator-sponsored clinical trials.

The presentations during this years annual meeting include data from the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin in combination with chemotherapy in frontline advanced classical Hodgkin lymphoma patients.

Based on the positive results from the ECHELON-1 trial, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to ADCETRIS in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin lymphoma.

During the annual meeting numerous oral and poster presentations will highlight additional progress within the brentuximab vedotin development program including:

  • Updated durability results from the phase III ALCANZA clinical trial in patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma, the most common subtypes of cutaneous T-cell lymphoma (CTCL). Based on the positive results from the ALCANZA trial, a supplemental BLA for brentuximab vedotin in CTCL was accepted for filing by the FDA. The FDA granted Priority Review for the application and the Prescription Drug User Fee Act (PDUFA) target action date is December 16, 2017. brentuximab vedotin previously received FDA Breakthrough Therapy Designation in this setting;
  • Updated results from a phase I/II study of brentuximab vedotin in combination with the ahuman programmed death receptor-1 (PD-1) blocking antibody nivolumab (Opdivo®; Bristol-Myers Squibb Company) among patients with relapsed or refractory Hodgkin lymphoma;
  • Final five-year survival and durability results in patients with CD30-expressing peripheral T-cell lymphomas who received brentuximab vedotin with cyclophosphamide, hydroxydaunorubicin, and prednisone (CHP) as frontline therapy

“At this year’s ASH Annual Meeting, we will present data from 18 abstracts, highlighting several [brentuximab vedotin] clinical program advancements that support our plans to establish ADCETRIS as the foundation of care for CD30-expressing lymphomas,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Importantly, the results of the phase III ECHELON-1 clinical trial evaluating brentuximab vedotin combination therapy in frontline advanced Hodgkin lymphoma patients was selected from over 6,000 abstracts submitted to be featured in the Plenary Scientific Session. These data are the basis for our planned supplemental biologics license application to the FDA requesting approval of brentuximab vedotin in this setting. The breadth of data being presented with brentuximab vedotin in CD30-expressing lymphomas demonstrates the power of antibody-drug conjugates with a goal of improving patient outcomes,” Siegall added

Brentuximab vedotin is currently not approved for the treatment of frontline Hodgkin lymphoma, CTCL, or as combination therapy for Hodgkin lymphoma or non-Hodgkin lymphoma.

For an overview of oral and poster presentations about antibody-drug conjugates, click here.

Ado-trastuzumab emtansine is currently the only antibody-drug conjugate available for the treatment of solid tumors.

In 2000 gemtuzumab ozogamicin, a calicheadmicin conjugates, became the first aDC to be approved in the United States. However, the drug, indicated for the treatment of CD33-positive acute myeloid leukemia (AML) was withdrawn from the market in 2010 due to treatment-related toxicity concerns.

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