With two approved antibody-drug conjugates and a large number of  ADCs in clinical development scientists have made significant advances bringing novel ADC technology to the forefront of drug development. Most of the advances observed are made possible through improved drug conjugation technologies and better tumor targeting.

During the upcoming annual meeting of the American Society of Clinical Oncology (ASCO), being held June 3-7, 2016 in Chicago, Astellas will present trial results of two investigational antibody-drug conjugates (ADCs) in patients with metastatic urothelial cancer.

In the United States, urothelial cancer of the bladder is the 4th most common cancer in men and the 9th most common in women, leading to 14,330 new deaths annually. [1] The disease accounts for 90%  of all bladder cancers.

Although newly diagnosed tumors are, in most cases, still superficial, up to 25% initially present with muscle invasion, half of which will be metastatic disease. Furthermore, of tumors that are initially superficial, 20% will progress despite intravesical chemo- and immunotherapy and will become muscle-invasive.[2][3]

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Experts agree that single-agent therapy has generally failed to provide adequate results in the treatment of patients with advanced, metastatic urothelial cancer.

The established standard of care for first-line therapy, gemcitabine + cisplatin or methotrexate, vinblastine, doxorubicin + cisplatin in platinum-eligible patients. For patients who cannot be treated with cisplatin, carboplatin–paclitaxel or gemcitabine– carboplatin are being considered as an alternative. Overall, in patients who recur or who are refractory to first-line therapy, response rates and outcomes are very grim, and to date, no second-line therapy has been clearly established.

Although survival rates may increase with early diagnosis and the introduction of neoadjuvant therapy before surgery new treatments are still needed as recurrence rates are high even after intensive therapy.[4][5]

As a result, there is a large unmet medical need.

Investigational agents
Using suppressive subtractive hybridization scientists at Astellas discovered SLITRK6, a member of the SLITRK family of neuronal transmembrane proteins, as a bladder tumor antigen. The scientists further showed that SLITRK6 is highly expressed in noninvasive and invasive bladder cancer as well as in a subset of lung cancer, breast cancer, and glioblastoma specimens.

Following discovery, the scientists developed ASG-15ME* (Product name AGS15E), a potent Monomethyl Auristatin E (MMAE)-based antibody-drug conjugate specific for SLITRK6 designed to meet the needs of bladder cancer patients.

ASG-15ME, which in multiple xenografts showed induced potent inhibition, and even tumor regression and currently in Phase I clinical trials, is composed of a SLITRK6-specific human gamma 2 antibody (Igγ2) conjugated to MMAE via a protease-cleavable valine-citrulline (vc) dipeptide linker. Each ADC has a drug-to-antibody ratio (DAR) of approximately 4:1.

ASG-15ME vs ASG-15MF: selecting a payload
When comparing ASG-15ME vs. ASG-15MF head-to-head trials, scientists observed activity with AGS-15MF in bladder tumor models, However, they also noted that ASG- 15ME showed consistently higher activity, leading to  tumor regression when AGS-15MF only caused tumor growth inhibition.  Since the AGS-15MF was still significant they compare the activity of MMAE versus MMAF as there was evidence that the choice of a non-cleavable linker may be better than a cleavable linker in some tumor types.

Scientists at Astellas selected, based on the high potency of ASG- 15ME in regressing tumors with homogenous and heterogeneous expression as well as other data, MMAE as the payload for their novel ADC.

Bystander effect
One of the reasons why they selected MMAE as their preferred payload was the activity seen in non-homogenous tumors. In addition to killing antigen-expressing cells, some ADC with cleavable linkers are found to kill bystander cells irrespective of their antigen expression. [6] This, so-called, “bystander killing” is an effect whereby cells that do not express the target, or express low levels of that target, are killed.  For example, MMAE, once cleaved, can diffuse across cell membranes and enter other cells in the tumor environment, killing bystander cells.

In unrelated preclinical studies researchers at Seattle Genetics developed a robust admixed tumor model consisting of CD30(+) and CD30(-) cancer cells to study how heterogeneity of target antigen expression affects treatment. They found that CD30-targeting antibody-drug conjugates delivering membrane permeable MMAE or pyrrolobenzodiazepine dimers demonstrated potent bystander killing of neighboring CD30(-) cells. [7]

In contrast, this type of bystander killing is not as likely seen with Monomethyl Auristatin F (MMAF)-based conjugates. One reason is that MMAF is a less membrane permeable payload which generally failed to mediate bystander killing in vivo. This “failure” is caused by the fact that MMAF was designed to have an additional carboxyl group giving it a negative charge at neutral pH.[8]  An additional reason is that MMAF is linked via a non-cleavable maleimidocaproyl linker.  The released active metabolite is a cysteine-linker-MMAF (cys-MMAF), which retains the charged amino and carboxyl groups of the amino acid.  In turn, charged carboxyl and amino groups make MMAF metabolites less able to diffuse across the cell membrane [9][10][11]

Scientists at Astellas believe that this difference in membrane permeability, is one of the primary causes of the observed difference seen between the activity of ASG-15ME and AGS-15MF in xenograft models with non-homogenous SLITRK6 expression.

ASCO Presentations
On Monday June 6 (1:00 – 4:30 PM), Daniel Peter Petrylak, MD, of Yale University will discuss the anti-tumor activity, safety and pharmacokinetics of AGS15E (ASG-15ME) in a phase I dose escalation trial (Abstract 4532).

This presentation is followed by a presentation by Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center discussing anti-tumor activity, safety and pharmacokinetics of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial.

Enfortumab vedotin comprises the human anti-nectin-4 antibody, conjugated to monomethyl auristatin E (MMAE) via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker. Nectin-4 (LNIR protein) is an antigen expressed expressed in multiple types of solid tumors

Scientists at Astellas are developing AGS15E and ASG-22CE under a collaboration with Seattle Genetics.

“Our activity at this year’s ASCO annual meeting underscores our immense commitment to helping those living with cancer,” noted Stephen Eck, MD, vice president and interim head of global oncology development, Astellas.

“Building on our foundation in non-small cell lung, pancreatic and advanced prostate cancers, we are continuously focused on identifying innovative ways to address the unmet needs of patients and caregivers facing cancer every day,” he continued.

In addition to data of novel ADCs, the company is expected to present on early phase data for ASP8273 in patients with EGFR mutation positive non-small cell lung cancer (NCSLC), gilteritinib pharmacokinetics and pharmacodynamics in patients with relapsed or refractory acute myeloid leukemia.

A selection of non ADC abstracts to be presented during poster sessions include:

  • Abstract 9050: Antitumor Activity of ASP8273 300mg in Subjects with EGFR Mutation-Positive Non-Small Cell Lung Cancer: Interim Results from an Ongoing Phase 1 Study. Presented by: Helena Alexandra Yu, MD, Memorial Sloan Kettering Cancer Center. Session Date/Time: Saturday, June 4, 8:00-11:30 a.m. CDT. Location: Hall A
  • Abstract 7026: Pharmacokinetics and pharmacodynamics of gilteritinib in patients with relapsed or refractory acute myeloid leukemia. Presented by: Catherine Choy Smith, MD, University of California San Francisco. Session Date/Time: Monday, June 6, 8:00-11:30 a.m. CDT Location: Hall A

Note: * ASG-15ME is the name used for AGS-15C after conjugation with valine-citrulline MMAE (vcMMAE) and AGS-15MF is the name for maleimidocaproyl MMAF (mcMMAF) conjugated AGS- 15C.

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