Demonstrating Results with Antibody-Drug Conjugates

Though antibody-drug conjugates (ADCs) have had a difficult time getting off the ground, their mechanism of action shows great potential for neutralizing cancer cells. Drug developers are focusing on manufacturing improvements to address some potential safety concerns posed by ADCs, as they work to demonstrate clinically significant therapeutic benefits.

Currently, only four ADCs have been approved by the FDA for sale in the United States:

• Adcetric (brentuximab vedotin), developed by Seattle Genetics, which was approved in August 2011

• Genentech’s Kadcyla (ado-trastuzumab emtansine), which was approved in February 2013

• Besponsa (inotuzumab ozogamicin), which was developed by Pfizer and approved in August 2017

• Mylotarg (gemtuzumab ozogamicin), also developed by Pfizer, which FDA approved a second time in September 2017 after Pfizer voluntarily withdrew the drug from the market after its initial FDA approval in May 2000. The withdrawal was due to the company’s inability to verify a clinical benefit with the product soon after the initial approval in 2000. There were also safety concerns under consideration (1) and because of safety concerns. 

Targeting cancer

ADCs are made up of an antibody that is linked to a cytotoxic agent by a biodegradable compound. While they are designed to eliminate fast-growing cancer cells, ADCs can also harm healthy proliferating cells, resulting in adverse patient reactions and side effects. Manufacturers are discovering different ways to reduce these side effects by finding different ways to configure the antibody and the chemotherapy portions of the compound. In some cases, for example, the entire ADC may be linked with a second cytotoxic agent, an approach that is allowing some ADCs to target cancer cells directly while avoiding harm to surrounding healthy cells (2).

The antibody component of the ADC is specific to tumor cell-surface proteins, which give ADCs tumor specificity and a potency that was previously believed to be impossible to achieve with traditional drugs. Ongoing ADC development efforts are now focusing on identifying better targets, determining more effective cytotoxic payloads, and further improving the way that the antibody and cytotoxic drug are linked. Improving the understanding of the mechanistic basis by which ADCs act should allow drug manufacturers to design rational combinations of ADCs with other agents, including immunotherapy treatments (3).

Challenges to development

Developing ADCs has been particularly challenging. In order for the compound to outperform an ordinary chemotherapy drug, the ADC must:

• Be able to target cell-surface proteins with tumor-specific membrane expression

• Be stabilized by a linker that keeps the cytotoxic payload attached during circulation but permits release of the load after cellular internalization

• Contain a cytotoxin that effectively kills tumor cells (3).

Early development of ADCs was hampered by several pharmacological and safety issues. A key factor was conjugation stability, according to David Simpson, CEO of Iksuda Therapeutics, a UK-based company that specializes in creating next-generation ADCs. The molecule’s inherent instability can lead to premature release of the cytotoxic payload, with profoundly negative effects on the therapeutic index (TI). The ultimate result is reduced efficacy and tolerability, Simpson explains.

Iksuda addresses molecular instability in ADCs in a number of different ways, including through its use of PermaLink conjugation technology, which results in a simple yet fundamental change in chemistry. The result: highly stable ADC constructs, developed via a concept the company terms “stability by design.”

“Iksuda’s cysteine-specific, vinyl pyridine platform has been validated in a range of conjugated drug models, including Iksuda’s lead ADCs, and clearly demonstrates that improved conjugation reaches a significant inflection point in both ADC efficacy and tolerability profiles,” Simpson states.

The overall “power” of ADCs also remains a major hurdle to development. This “power” is driven by “the payload’s ability to elicit its potent cell-killing activity in a broad range of tumor types-ultimately targeting the broadest possible patient population,” Simpson says. He notes that the industry currently has limited availability of payloads that are proving safe and effective in the clinic. Nevertheless, manufacturers continue to strive for ultra-potent toxin classes with novel modes of action to combat the emergence of drug resistance and the ongoing challenge of treating unyielding solid tumors.

“By focusing its attention on this challenge, Iksuda has leveraged the stability of the PermaLink conjugation platform to gain access to potent DNA alkylating payloads, incorporated into its lead ADC, as well as developing its own proprietary ultra-potent payload platform with a previously untapped mode of action for future ADC programs,” says Simpson.

Cancer-killing mechanism

As an emerging class of targeted therapeutics, ADCs have the potential to improve TI over traditional chemotherapy. “By combining the targeting power of antibodies with the cell-killing capability of potent cytotoxic molecules, it is possible to kill cancer cells more effectively while reducing debilitating side effects,” notes Simpson.

In broad terms, the anti-cancer activity of an ADC is driven by the toxicity of its payload and tolerability in patients depends on the stability of the conjugation chemistry and tissue distribution of the antigen (i.e., whether the target is present in healthy tissue or not). “This tumor-directed delivery system is designed to reduce off-target toxicity by limiting exposure of normal tissues to the cytotoxic payload. Stable conjugation chemistries (e.g., PermaLink), novel mechanisms of action, and highly potent toxins are being developed to increase the TI of ADCs,” he states.

Meanwhile, the limitation of antibodies has been their ability to complement their highly specific targeting capabilities with an equally matched ability to induce apoptosis. “An ADC’s ability to effectively exploit the targeting capabilities of the antibody whilst ‘supercharging’ its cell-killing capabilities by the addition of a cytotoxic payload has broadened the application for the use of antibodies and revolutionized the use of alternative targeting moieties and scaffolds. The combined success of these therapeutic classes will dramatically improve the therapy options for cancer and particularly those of an aggressive nature,” according to Simpson.

The ADC field has been quick to respond to the rapidly shifting oncology drug preferences, which are now focusing on combination therapies. Checkpoint inhibitors had raised hopes for improved clinical outcomes. Despite their early promise, these drugs have shown variable effectiveness in treating solid tumors, and are more effective when used in combination with another therapeutic. ADCs might show considerably greater efficacy when used in combination with existing treatment regimens to give greater efficacy, and this approach would not worsen any debilitating side effects, Simpson points out.

By using the antibody’s ability to specifically target tumor tissue rather than healthy, normal tissue, ADCs can deliver highly potent cytotoxic payloads directly to the tumor site. “ADCs allow clinicians to target solid tumors specifically, with previously unobtainable dose levels of the active, cell-killing reagent, without exposing healthy tissue to its affects. Iksuda’s approach to conjugation chemistry allows manufacturers to enable the safe use of ultrapotent cytotoxic payloads. It thus raises the bar on the TI of ADCs and their clinical benefits to patients,” remarks Simpson.

Regulatory consideration

Composed of both biologic and small-molecule components, ADCs are complex entities. Their regulatory review also follows a complex path that has been specifically designed to ensure patient safety, Simpson explains.

“ADCs require review by both the Office of New Drug Quality Assessment (ONDQA) and the Office of Biological Products (OBP). Both offices have responsibility for Drug Substance and Drug Product and as with any emerging product class, ADC developers have worked closely with FDA to develop and drive the regulatory pathway,” he says, pointing out that the yearly increase in investigational new drug submissions for ADCs is a testament to the dedication of both drug developers and regulatory bodies to prove the value of these therapeutics in the clinic.

“To date, and with the notable exception of the currently approved products, the therapeutic window for ADCs remains disappointing. In the recent past, clinical trials have been discontinued due to dose-limiting toxicities. This was seen with rovalpituzumab tesirine [Rova-T] and vadastuximab talirine, for example, each of which has a pyrrolobenzodiazepine dimer payload),” he says. However, he believes that ADCs present a valuable and viable opportunity in the armoury against cancer, drug developers continue to reflect and learn from success and, importantly, failure in order to develop ADCs with sufficiently wide TI.

Next-gen hopes

Drugmakers that are working on optimizing ADCs are learning from past failures as they continue to push for innovation, in the form of next-generation ADC drug development. As a result, the next generation of ADC is broadly considered to have a significantly wider therapeutic window, Simpson remarks.

These next-generation ADCs are more stable, contain highly potent payloads with broad activity, and are more homogeneous than the previous generation. Therefore, they are less influenced by differential clearance rates when compared to those ADCs that are currently well advanced in clinical development programs. “While the field recognizes that there is no ‘one box for all’ approach for ADCs, significant focus has been given to site-specific conjugation which allows for a homogeneous ADC that is generally more systemically stable with a concomitant improvement in PK [pharmacokinetics],” Simpson says.

Even though only four ADCs are on the market, Simpson notes that more than 40 site-specific drug conjugate technologies have been developed. While the ADC field has historically been dominated by the use of auristatins (e.g., monomethyl auristatin, or MMAE) and maytansines (e.g., DM4), next-generation ADCs are moving toward more potent payloads with DNA damagingmechanisms of action. Examples include duocarmycins, pyrrolobenzodiazepine dimers, and indolinobenzodiazepine dimers).

References

1. Pfizer, “Pfizer Receives FDA Approval for Mylotarg (gemtuzumab ozogamicin),” Press Release, Sep. 1, 2017.
2. P. Holland, “The Next Advancements in Cancer Drug Development: Antibody-Drug Conjugates,” adcreview.com, June 14, 2012.
3. IQVIA, “Antibody Drug Conjugates in Cancer Drug Development,” White Paper, iqvia.com, 2017.

Article Details 

BioPharm International
Vol. 32, No. 4
April 2019
Pages: 14–16 

Citation 

When referring to this article, please cite it as F. Mirasol, “Demonstrating Results with Antibody-Drug Conjugates," BioPharm International 32 (4) 2019.