ADC Development Robust Despite Lackluster Performance
molekuul_be/Shutterstock.com
Focus on the development of antibody drug conjugates (ADCs) remains robust as drug companies continue to invest resources in this area of therapeutics. The road to market has been difficult, however, with only three ADC products approved for sale by FDA in the United States as of October 2017. This has not stopped ADC developers, though, and the biopharmaceutical pipeline is populated with ADC candidates under development.
The promise of conjugation
ADCs are part of a relatively new class of targeted cell immunotherapeutics that represent a major step in developing precision drugs (1). The target for ADCs has primarily been cancer, and the cytotoxic agents that are used in ADCs are typically more potent than currently used anti-cancer drugs (1).
The ADC construct combines a targeted monoclonal antibody (mAb) with a cytotoxic agent, linked together with a stable linker technology. An ADC enables the specific delivery of chemotherapeutics to tumors while avoiding systemic exposure to the cytotoxic compound (1).
Because the stable linkers conjugate cytotoxic molecules to the mAb, ADCs can remain inactive while in circulation within the patient’s body. The agent is internalized by the tumor cell after it is bound to the cell by the mAb end of the ADC molecule. Inside the tumor cell, the ADC breaks down into its components, which releases the cytotoxic agent inside the cell, thereby killing it (1).
“The potential of ADCs has been enhanced by a greatly expanded knowledge of ADC technology, cancer biology, and pharmacology. It is projected that the global market for ADCs will reach $2.8 billion by 2018,” said Mirella Zulueta, business development director at Oncomatryx, a Spain-based biopharmaceutical company focused on tumor stroma, in a company blog (1).
ADCs on the market now
Currently, there are only three ADCs approved by FDA for the US market. These three, from Pfizer, Roche, and Seattle Genetics, are all indicated for treating cancers.
Pfizer’s product, Mylotarg (gemtuzumab ozogamicin), was approved in 2017, nearly a decade after an initial approval in 2000 (2). Soon after its first approval by FDA in 2000, Pfizer voluntarily withdrew Mylotarg from the market because the company was unable to verify a clinical benefit and because of safety concerns. The more recent approval authorizes the use of the drug for treating acute myeloid leukemia (AML).
Roche’s product, Kadcyla (trastuzumab emtansine), was approved by FDA in 2013. It is indicated for treating HER2-positive, metastatic breast cancer. The drug is among Roche’s top-10 selling products, earning 2016 sales of CHF 831 million (US$844 million) (3).
Seattle Genetics’ product, Adcetris (brentuximab vedotin), was approved in 2011. It is indicated for treating classical Hodgkin lymphoma (cHL) and systemic anaplastic large cell lymphoma (ALCL). Adcetris had 2016 sales of approximately $266 million (4).
Optimism in the pipeline
Despite the promise of ADCs as an alternative therapeutic for cancers, response rates to these drugs in clinical trials have been typically low, and in addition, toxicity issues have been common. This has led to an unfavorable attitude toward ADCs for some industry participants. Overall, however, the industry continues to believe in the clinical benefits of these drugs (1). Some examples of ADCs in clinical development include candidates from Seattle Genetics, Immunomedics, and Roche. In addition, companies such as Mersana Therapeutics and Oncomatryx are using different approaches to ADC development.
Seattle Genetics. Seattle Genetics is among the companies developing a pipeline that highlights ADCs (5). In addition to having Adcetris on the market for cHL and ALCL, the company is also further developing the ADC for other indications, including in three Phase III clinical studies to evaluate its potential in earlier lines of treatment within its already approved indications (6).
In addition, the company is developing brentuximab vedotin, the active ingredient in Adcetris, in many additional types of CD30-expressing lymphomas, including cutaneous T-cell lymphoma, mature T-cell lymphomas--commonly referred to as peripheral T-cell lymphoma--and B-cell lymphomas (6).
Seattle Genetics is developing brentuximab vedotin in collaboration with Takeda Pharmaceutical, under which Seattle Genetics has the commercialization rights in the US and Canada while Takeda has commercialization rights in the rest of the world. Joint worldwide development costs are funded equally between the two companies, except in Japan where Takeda has full responsibility for development costs (6).
Seattle Genetics has an ADC candidate in Phase II development as well: denintuzumab mafodotin. This candidate is in two Phase II trials for relapsed/refractory and frontline diffuse large B-cell lymphoma (7). Also approaching Phase II development is enfortumab vedotin, an ADC that the company is co-developing with Japanese pharmaceutical firm Astellas Pharma. This ADC is expected to go into a Phase II trial in metastatic urothelial cancer in the second half of 2017 and has been undergoing a Phase I trial evaluating its safety and antitumor activity in escalating doses for metastatic urothelial cancer (8).
Seattle Genetics also has several other ADC programs in early-stage clinical development, including candidates for cervical cancer, metastatic breast cancer, metastatic urothelial cancer, relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, relapsed/refractory AML, and relapsed/refractory multiple myeloma (5).
Immunomedics. Immunomedics, a clinical-stage biopharmaceutical company based in Morris Plains, NJ, specializes in antibody-based therapeutics and has two ADCs in clinical development. Sacituzumab govitecan is a Phase II ADC candidate in development for metastatic triple-negative breast cancer (TNBC) and metastatic solid cancers, including lung, urothelial, and esophageal (9). Labetuzumab govitecan is the second ADC, also in Phase II clinical development. It is being developed for metastatic colorectal cancer (9).
In February 2016, FDA granted breakthrough therapy designation to sacituzumab govitecan for the TNBC indication. The agency also awarded the ADC a fast-track designation. If approved, the ADC will join Eisai’s eribulin, for treating metastic liosarcoma, and Novartis’ ofatumumab, for treating recurrent or progressive chronic lymphocytic leukemia, both of which were approved in 2016 (10).
Roche. Although it is not currently conducting clinical development of new ADCs in its pipeline, Roche is further developing its already-approved ADC, Kadcyla, by pairing it up in clinical trials with other anti-cancer agents.
In one Phase III clinical trial, the company is studying Kadcyla in combination with its anti-breast cancer biologic Perjeta (pertuzumab) as an adjuvant treatment for early-stage HER2-positive breast cancer. In a Phase II trial, the company is evaluating the combined use of Kadcyla with its anti-cancer biologic Tecentriq (atezolizumab) as a second-line treatment for HER2-positive metastatic breast cancer. The company plans to submit regulatory filings for these indications in 2020 or later (11).
In addition to these combination-use clinical trials, Roche is also conducting two Phase III clinical trials for Kadcyla in the third-line and adjuvant treatment of HER2-positive metastatic breast cancer. The company plans to file a regulatory submission for the adjuvant treatment indication in 2020 or later, but has not specified a timeline for regulatory filing of the third-line treatment indication (11).
Different approaches to building an ADC
Due to past failures in efficacy, safety, and tolerability, other ADC developers are looking deeper into the ADC conundrum to come up with different approaches on how an ADC can be made and what it should do. Two examples include a company that developed a water-soluble polymer that can enhance the effectiveness of an ADC and another company that chooses a target outside of, but significantly associated with, tumor cells.
Mersana Therapeutics. Cambridge, MA-based Mersana Therapeutics, a clinical-stage company, is developing an ADC pipeline across multiple tumor types. Its lead ADC candidate, XMT-1522, is in Phase I clinical development for tumors expressing the HER2 antigen (12).
The candidate is built on the company’s lead ADC platform, Dolaflexin, which consists of a biodegradable, biocompatible, and water-soluble polymer, called Fleximer, and multiple molecules of the company’s proprietary drug payload, auristatin, which are attached to Fleximer by a linker specifically designed to work with this polymer (13). Takeda has the rights to XMT-1522 outside the US and Canada under a strategic partnership it entered with Mersana in February 2013 (14).
Mersana’s technology aims to enhance the efficacy, safety, and tolerability of ADCs. Because its polymer is highly water soluble, it can be used to surround the cytotoxic payload and compensate for the payload’s poor solubility, thus minimizing aggregation and maintaining the ADC’s stability while in circulation (13). Multiple molecules of this polymer-payload construction (Dolaflexin) can then be attached to the chosen mAb, which results in an ADC with a significantly increased payload capacity, according to the company.
Mersana’s approach differs from other ADC technologies in which the cytotoxic payload is directly conjugated to the mAb using a linker. With the company’s Dolaflexin platform, ADCs can be produced that carry a drug-to-antibody (DAR) ratio between 12 to 15--a three to four-fold increase in DAR compared to traditional ADC constructs--and still maintain pharmacokinetics and drug-like properties within an acceptable range, as demonstrated in animal models (13).
In addition to its XMT-1522 lead candidate, the company is also developing XMT-1536, another ADC created on its Dolaflexin platform, which is in the pre-clinical phase and for which an investigation new drug application was filed. The latter is targeting tumors expressing the NaPi2b antigen, which is highly expressed in 75% to 90% of non-squamous non-small cell lung cancer and epithelial ovarian cancer cells (12).
The NaPi2b antigen was evaluated as a target for an ADC (lifastuzumab vedotin) by Genentech, a Roche company (12). Mersana expects to enter into clinical trials for XMT-1536 in early 2018.
In addition to these two ADC programs in development, as well as two other early drug discovery-stage ADC programs, Mersana partnered with EMD Serono, the life-sciences business of Merck KGaA, in 2014 to develop next-generation ADCs using Mersana’s ADC technology (15). Mersana is generating Fleximer-ADCs using mAbs provided by EMD Serono. Mersana will also conduct drug discovery and pre-clinical development activities, while EMD Serono will be responsible for clinical development and commercialization of any products that result, as per an exclusive license granted by Mersana (15).
Similarly, Mersana has a collaboration with Takeda to develop ADCs. In February 2016, the companies expanded an already existing collaboration between them. The expanded deal provides Takeda with additional access to Mersana’s Fleximer technology (14). Mersana has an option to co-develop and co-commercialize programs from its partnership with Takeda when Phase I clinical development is completed. The companies will also co-develop new cytotoxic payloads to use in ADCs (14).
Oncomatryx. The Spanish ADC-focused company, Oncomatryx, specializes in precision drugs that target the tumor stroma, that is, the supportive microenvironment that surrounds tumor cells.
Oncomatryx’s approach is to develop precision drugs that target proteins located in the tumor microenvironment, which it believes is a novel route to cancer treatment because it is directed at stromal cells that propagate the invasiveness, immune suppression, and drug resistance of tumor cells, rather than directed at the epithelial cells of the tumor (16).
The company has developed a pipeline of ADCs, as well as antibodies and human-derived proteins, that target the tumor-associated stroma. For its ADC development, the company is developing antibodies that specifically target two stromal-cell membrane proteins, MTX5 and MTX3 (17,18).
The first of these targets, MTX5, is a membrane glycoprotein found in fibroblasts associated with cancer. However, Oncomatryx’s approach is not to block MTX5, because blocking this protein was shown to be ineffectual in previous Phase II studies. Instead, the company’s approach is to use the protein as a cancer-associated-fibroblast-specific vehicle to internalize cytotoxic molecules because MTX5 is naturally capable of internalizing molecules (16). Similarly, the other target, MTX3, is a membrane protein found in endothelial cells that also possesses a natural ability to internalize molecules (17).
The cytotoxic payloads that Oncomatryx is developing are cytolysin and nigrin. The company has designed three cytolysin molecules that will be conjugated to mAbs. With nigrin, the company has developed two payloads: a nigrin b-A chain molecule and a recombinant version of the nigrin b-A chain. Nigrin b is a plant toxin derived from the bark of an elder plant (Sambucus nigra) (19). The company’s first ADC clinical candidate, OMTX705, is being developed for pancreatic cancer and invasive lung and breast cancer. The company has already run pre-clinical trials on the candidate (20).
References
1. M. Zulueta, “Antibody Drug Conjugates Against Tumor Stroma: The Beginning of the End? [2],” accessed Oct. 23, 2017.
2. Pfizer, “Pfizer Receives FDA Approval for Mylotarg (gemtuzumab ozogamicin) [3],” Press Release (Sep. 1, 2017).
3. Roche, “Annual Report 2016 [4],” accessed Oct. 20, 2017.
4. SEC, “Seattle Genetics Form 10-K [5],” accessed Oct. 20, 2017.
5. Seattle Genetics, “Strong Development Pipeline [6],” accessed Oct. 23, 2017.
6. Seattle Genetics, “Brentuximab Vedotin [7],” accessed Oct. 23, 2017.
7. Seattle Genetics, “Denintuzumab Mafodotin [8],” accessed Oct. 23, 2017.
8. Seattle Genetics, “Enfortumab Vedotin [9],” accessed on Oct. 23, 2017.
9. Immunomedics, “Pipeline [10],” accessed Oct. 24, 2017.
10. BioPharm International, “Immunomedics Receives Breakthrough Therapy Designation for Breast Cancer Antibody-Drug Conjugate [11],” accessed Oct. 24, 2017.
11. Roche, “Product Development Portfolio [12],” accessed Oct. 24, 2017.
12. Mersana Therapeutics, “Pipeline [13],” accessed Oct. 23, 2017.
13. Mersana Theraputics, “Our Technology [14],” accessed Oct. 23, 2017.
14. Takeda Pharmaceutical, “Mersana Therapeutics and Takeda Expand Partnership to Advance Development of Fleximer Antibody-Drug Conjugates and XMT-1522 [15],” Press Release (Feb. 3, 2016).
15. BioPharm International, “EMD Serono and Mersana to Develop Next-Generation Antibody-Drug Conjugates [16],” accessed Oct. 24, 2017.
16. Oncomatryx, “Our Battlefield, the Stroma [17],” accessed Oct. 24, 2017.
17. Oncomatryx, “Targets: MTX5 & MTX3,” http://oncomatryx.com/antibody-drug-conjugates/targets-mtx5-mtx3/ [18], accessed Oct. 24, 2017.
18. Oncomatryx, “Antibodies: MTX5 & MTX3 [19],” accessed Oct. 24, 2017.
19. Oncomatryx, “Payloads: Cytolysin & Nigrin [20],” accessed Oct. 24, 2017.
20. Oncomatryx, “Pipeline [21],” accessed Oct. 24, 2017.