Harnessing the Power of Three: Advancing Antibody-Drug Conjugates from Laboratory to Bedside

June 1, 2013 | Peter Hofland, Ph.D | Executive Editor and Publisher | doi: 10.14229/jadc.2013.6.1.001

Received May 9, 2013 | Accepted May 29, 2013 | Published online June 1, 2013

Abstract
Antibody-drug conjugates or ADCs are creating much excitement among life science professionals, medical/clinical research scientists and pharmaceutical specialists. At the same time, oncologists and hematologists are eager to welcome new treatment options in the ongoing war against cancer. This article reviews some of the advances made in the development of ADCs.


Considered by many as the “next generation” of anticancer therapy, ADCs are composed of a tumor-specific cancer cell-targeting monoclonal antibody (mAb) linked via a chemical linker to a cytotoxic agent or “payload” with a validated mechanism of action, such as a highly potent microtubule disrupting or DNA-modifying agent.

ADCs offer a great advantage over existing conventional chemotherapy, which has been around since the 1940s. Due to a lack of selectivity, drug concentrations of conventional chemotherapy, although often able to eradicate a tumor, cannot be used in many cases because they surpass the maximum tolerable dose or damage healthy tissue. After prolonged treatment, they can also become ineffective when the tumor develops multidrug resistance.[1] On the other hand, “naked” antibody therapy offers great specificity but lacks sufficient potency to kill cancer cells. Researchers realized that by marrying the two concepts, they could potentially solve the drawbacks of both treatments and develop a new therapeutic approach.    

Because they are designed to specifically attach to cancer cells with their unique target-specific receptors, ADCs do not affect the healthy cells that lack these specific receptors. As a result, the cytotoxic agent, as part of the conjugate drug, can be much more potent–as much as a thousandfold--than systemic chemotherapeutic agents, thus allowing normally intolerable doses of cytotoxic drugs to be used in anticancer therapies.

A simple concept
By harnessing monoclonal antibodies to deliver cytotoxic payloads to tumor cells, ADCs are a step closer to becoming the “magic bullets” against cancer, a concept first envisioned and popularized more than 100 years ago by the German physician, scientist and Nobel laureate Paul Ehrlich (1854–1915). While the concept is simple, the realization of clinically approved and successful ADCs has not been easy.

Early in the development of ADCs, researchers found that three factors were critical for the potential of therapeutic success:

  • The stability of the chemical linker connecting the cytotoxic to the
monoclonal antibody; linkers that are too stable result in low potency, while linkers that are not stable enough lead to high systemic toxicity
  • Internalization in the target cell.
  • Release of the cytotoxic agent.

Failure and success
While antibodies used against various tumor antigens have been linked to radioisotopes (radio-immunotherapy), toxins (immunotoxins) and cytotoxic agents since the 1960s and early 1970s, the development of clinically approved ADCs has taken decades.[2]

The observation of antigen expression by tumor cells in the 1960s fostered a fundamental understanding of the potential of antibody-based therapies to combat cancer.[2] Based on these early observations, researchers concluded that antibodies could also be used to deliver cytotoxic drugs directly to cancer cells.[3,4] Building on this finding, clinical trials with murine immunoglobulin G (IgG) were conducted in the 1980s. While these initial attempts were not always successful, high-profile failures led to innovations and significant improvements in monoclonal antibody engineering and drug/linker technology.

In the 1990s, scientists at Bristol-Myers Squibb covalently linked doxorubicin (Adriamycin®/Rubex®), an intercalating chemotherapeutic agent that blocks DNA replication, to the humanized monoclonal antibody BR96.[5] Doxorubicin was connected with the hydrazone linker to cysteine residues of the Lewis-Y specific monoclonal antibody. The preclinical activities of the cBR96-doxorubicin conjugate (BMS-182248/SGN-15) were incredible, astonishing the researchers involved in the development project. But despite the use of eight drugs per monoclonal antibody molecule, the amount of conjugate needed to achieve the same remarkable effects in vivo was very high (>100 mg/kg). Researchers assumed that this was the result of the relatively low potency of doxorubicin. They also noted that the half-life of the drug in the bloodstream was short compared to the half-lives of several days to weeks of the naked BR96 monoclonal antibodies in humans. In the end, the compound failed to show sufficient clinical efficacy, and trials were terminated.[6]

Mylotarg – the first real ADC
The first authentic antibody-drug conjugate to reach the market was gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth). The compound was approved in May 2000 under the U.S. Food and Drug Administration’s accelerated approval program for the treatment of patients (≥60 years old) with recurrent acute myeloid leukemia (AML) who were not considered candidates for other chemotherapy.[7]  The initial legalization of gemtuzumab ozogamicin was based on “the surrogate endpoint of response rate,” or the percentage of patients whose disease decreased or disappeared in laboratory tests. These results, observed in 142 patients with AML, came from three different clinical trials that demonstrated a 30% response rate (including complete response or CR) and CR with incomplete platelet recovery.

The initial approval was conditional on the future demonstration of benefits from confirmatory trials that began in 2004.[8] The post-approval trials were designed to determine whether adding gemtuzumab ozogamicin to standard chemotherapy showed an improvement in clinical benefit (survival time) to AML patients. The trials were stopped early when researchers did not observe a clinical benefit, and after a greater number of deaths were observed in the group of patients receiving gemtuzumab ozogamicin compared to those receiving chemotherapy alone. The results of a randomized study by the Southwest Oncology Group (SWOG), one of the largest National Cancer Institute-supported cancer clinical trials cooperative groups, led to the voluntary withdrawal of gemtuzumab ozogamicin in 2010, when improved efficacy could not be demonstrated while toxicity appeared to be excessive.[9,10]

Mechanism of action
Gemtuzumab ozogamicin targets CD33 expressed on the majority of AML leukemic blasts. The drug links a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic, to a recombinant monoclonal antibody. In equal molar concentrations, calicheamicin is about 3,200 times more potent than doxorubicin hydrochloride, which is the approved standard therapy to be used alone or with other drugs to treat AML.[11] Unfortunately, in the case of gemtuzumab ozogamicin, the targeted receptor was not as selective as researchers once thought it to be. Also, the linker technology based on pH-dependent release mechanism was unstable, resulting in much of the cytotoxic drug being released too early.[6]

The development of monoclonal antibodies, cytotoxins and new chemical linkers to covalently bind all the building blocks of ADCs has made remarkable progress in the decade since the initial approval of gemtuzumab ozogamicin. Today, many of the concerns leading to the withdrawal of the drug have been addressed in the ongoing development of new therapies.

Linkers are fundamental
High-profile failures have shown the fundamental role of linkers. Early decomposition or decay causes the release of a highly potent cytotoxin before it can be delivered to the selected target site. Furthermore, to be effective, the cytotoxic drug must be completely and efficiently released in its active form after internalization. Proper linkage is also a key factor in determining therapeutic potential.[6] Ducry and Stump aptly describe how recent advances in the development of ADCs have resulted in the ability to create linkers with increased stability in the bloodstream, while limiting the damage caused to healthy tissue.[6]

New ADCs enter the market
Seattle Genetics’ brentuximab vedotin (Adcetris®/SGN-35) was approved by the FDA in 2011 for the treatment of non-Hodgkin’s lymphoma and anaplastic large-cell lymphoma.[12] Then, in early 2013, Genentech’s ado-trastuzumab emtansine /T-DM1 (Kadcyla™) was approved for the treatment of patients with HER2-positive metastatic breast cancer (mBC) who have received prior treatment with trastuzumab (Herceptin®; Genentech/Roche) and a taxane chemotherapy.[13]

Most ADCs in development make use of auristatins, such as monomethyl auristatin E (MMAE), an antimititic agent inhibiting cell division by blocking the polymerisation of tubulin from Seattle Genetics, and maytansines (highly potent antimicrotubule agents) from ImmunoGen. But other classes, such as extremely potent pyrrolobenzodiapines (PBDs) from Spirogen, are rapidly emerging.

During the recent World ADC meeting in Frankfurt, Germany, and the PEGS meeting in Boston, data were presented on novel ADCs in development. Among the exciting concepts discussed were Immunue Pharmaceuticals’ NanomAbs® platform, Mersana Therapeutics’ biodegradable flexible polymer linker technology and Ambrx site-specific conjugation, which has a significant impact on stability and pharmacokinetics.

Fulfilling the promise
ADCs now fulfill the promise of the specific delivery of cytotoxic drugs to tumor cells while avoiding the dose-limiting toxicity of chemotherapy that occurs because of its effects on normal cells. With a firmly established proof of concept, two approved ADCs, more than 50 candidates in clinical trials (albeit some in early-stage studies), and a great number of established companies--including Pfizer, BMS, Amgen, Novartis, Takeda/Millennium, MedImmune, Sanofi and other players jumping on the bandwagon--the medical community can look forward to a bright future for ADCs.

But much of the excitement would be unwarranted without specialized companies. For example, Lonza’s scientists are not only familiar with the newest ADCs but are actively developing innovations in both the biotechnology and chemistry of monoclonal antibodies and highly potent cytotoxic agents, linking the two to create industry-leading cancer therapeutics. With more ADCs entering the development pipeline and critical data from different projects being reported, these scientists can be better predict how these new therapies will perform in the clinic and which ones will ultimately make it to market.

By harnessing the power of three--antibody, linker and cytotoxic agent—the development and approval of ADCs is advancing rapidly, from basic research and the laboratory to clinical trials and the patient’s bedside. Over the next few years, the ongoing breakthroughs and growing number of available treatments promise to make the field even more exciting.

References
[1] Kovtun YV, Audette CA, Mayo MF, Jones GE, Doherty H, Maloney EK et al. Antibody-Maytansinoid Conjugates Designed to Bypass Multidrug Resistance. Cancer Res. March 15, 2010 70; 2528
[2] Rettig WJ. and Old, LJ Immunogenetics of human cell surface differentiation.  Annu. Rev. Immunol. 7, 481–511 (1989)
[3] Alley SC, Okeley NM, Senter PD Antibody-drug conjugates: Targeted drug delivery for cancer.  Curr. Opin. Chem. Biol. 2010, 14, 529–537.
[4] Hughes B Antibody-drug conjugates for cancer: Poised to deliver?  Nat. Rev. Drug Discov. 2010, 9, 665–667.
[5] Trail PA, Willner D, Lasch SJ., Henderson AJ, Hofstead S, Casazza AM, Firestone RA, Hellstro¨m I,Hellstro¨m KE. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261, 212–215 (1993).
[6] Ducry L, Stump B.  Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies 2010. Bioconjug Chem. Jan; 21(1):5-13. doi: 10.1021/bc9002019
[7] Bross PF, Beitz J, Chen G, et al.  Approval summary: Gemtuzumab ozogamicin in relapsed acute myeloid leukemia.  Clin Cancer Res 7:1490–1496 (2001)
[8] Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.  J Clin Oncol 19:3244–3254 (2001).
[9] Rowe JM, Löwenberg B.  Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood 2013, April 16 [Epub ahead of print]
[10] Petersdorf S, Kopecky K, Stuart RK, et al. Preliminary results of Southwest Oncology Group Study S0106: An international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia,” Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 790
[11] Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S et al., “Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia,” Clin Cancer Res. 2001 Jun;7(6):1490-6.
[12] Package Insert Adcetris® (brentuximab vedotin; Seattle Genetics, Inc. Last accessed: May 16, 2013
[13] Package Insert Kadcyla™ (ado-trastuzumab emtansine) for injection Last accessed: May 16, 2013

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