With promising data of brentuximab vedotin and inotuzumab ozogamicin leading the way, antibody-drug conjugates are beginning to make a greater impact on the lymphoma treatment landscape.
Brad S. Kahl, MD
With promising data of brentuximab vedotin (Adcetris) and inotuzumab ozogamicin (Besponsa) leading the way, antibody-drug conjugates (ADCs) are beginning to make a greater impact on the lymphoma treatment landscape.
“The rationale for ADCs is quite self-evident," said Brad Kahl, MD. "The goal is to deliver cytotoxic agents, and to deliver them more selectively. If you are able to achieve that, you can improve the therapeutic index, which would then, in theory, allow for the delivery of more potent cytotoxic agents that you could administer intravenously."
In a presentation on new ADCs during the 2018 Pan Pacific Lymphoma Conference, Kahl, a professor in the Department of Medicine, Washington University School of Medicine in St. Louis, Siteman Cancer Center, laid out the current use of ADCs in lymphomas, as well as novel agents coming down the pike.
To build an ADC, there must first be an antigen-antibody combination, then a linker, a conjugation, and finally a payload, Kahl explained.
"Antigens should be tumor-specific, internalized, and abundant—some data suggest that 10,000 antigens per tumor cell is the minimum. Then, you need a good monoclonal antibody to bind to that antigen,” said Kahl.
Examples of target antigens for ADCs currently under evaluation include CD19, CD22, CD25, CD30, CD37, and CD79b.
Linkers are short chemical spaces that bind the antibody to the drug, explained Kahl. The linker ends up being very important in the construction of an ADC, as it must be stable in circulation to inhibit the agent from moving freely in the patient. These linkers must be able to release the drug upon internalization, Kahl said.
There are 2 types of linkers: cleavable and non-cleavable. Cleavable linkers include hydrazones, which release payload under acid conditions of the lysosome; disulfides, which undergo thiol-disulfide exchange reactions; and peptides, which release payload after protease cleavage. Non-cleavable linkers allow the entire ADC to be degraded in a lysosome-releasing payload. These linkers are theoretically more stable in circulation, Kahl explained.
Conjugation focuses on the drug-to-antibody ratio (DAR). If there is too little drug in the antibody, potency can be lost; however, if there is too much, it can result in increased toxicity or hydrophobicity. Some data suggest that a DAR of 4 is optimal, said Kahl.
There are different ways to place the drug onto the antibody, he added. The heterogeneous payload placement method is the most common. It exploits the endogenous lysine or hinge cysteine residues. This is a nonspecific way to get the drug onto the antibody, as the DAR ranges from 0 to 8 per antibody, but it is more commonly used.
There is also the site-specific method, in which reactive chemical handles are place on the monoclonal antibody. This results in more control of DAR, Kahl said. Some of the newer ADCs in development are using this method.
Some of the payloads used in ADCs include microtubule inhibitors, such as auristatins and maytansines. There are also DNA damaging agents such as enediynes, duocarmycin derivatives, and pyrrolobenzodiazepines. Toxins can also be used, Kahl said, such as pseudomonas exotoxin and ricin.
"It is estimated that less than 2% of the payload administered actually localizes to the tumor cell when you are administering ADCs," Kahl said. "So, your payload must be very potent."The ADC brentuximab vedotin is approved in patients with relapsed/refractory Hodgkin lymphoma, CD30-positive anaplastic large cell lymphoma, high-risk Hodgkin lymphoma post-remission after autologous stem cell transplant, relapsed cutaneous T-cell lymphoma and myelofibrosis, and as a frontline therapy for Hodgkin lymphoma. The major toxicities associated with brentuximab vedotin include neuropathy, nausea, and fatigue.
Inotuzumab ozogamicin was approved by the FDA in 2017 for relapsed/refractory precursor B-cell acute lymphocytic leukemia (ALL). It is currently being evaluated in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and relapsed/refractory follicular lymphoma. Major toxicities linked with this ADC include myelosuppression, nausea, and fatigue.
Polatuzumab vedotin, a CD79b humanized monoclonal antibody cleavable peptide linker, is currently being investigated as a single agent, in combination with rituximab (Rituxan), in combination with bendamustine and rituximab (BR). It is also being tested in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with placebo in the POLARIX trial (NCT03274492).
Patients with relapsed/refractory follicular lymphoma and DLBCL are being evaluated in a randomized phase II trial of polatuzumab vedotin plus BR (NCT02257567). Polatuzumab is given at a dose of 1.8 mg/kg once daily with 90 mg/m2 of IV bendamustine every 2 days, and 375 mg/m2 of IV rituximab once daily. The patients with follicular lymphoma (n = 80) are undergoing six 28-day cycles, while those with DLBCL will under six 21-day cycles.
Kahl explained that the conclusions drawn from this trial thus far are that polatuzumab vedotin can be safely administered in combination with BR. There was no significant difference with short-term follow-up for patients with follicular lymphoma, but adding polatuzumab vedotin to BR improved response rates, progression-free survival (HR, 0.31; 95% CI, 0.18-0.55; P <. 0001), and overall survival (HR, 0.35; 95% CI, 0.19-0.67; P = .0008) in the DLBCL group regardless of prior lines of treatment or whether patients had refractory disease.
In 2017, the FDA granted a breakthrough therapy designation to polatuzumab vedotin for the treatment of people with relapsed or refractory DLBCL. The European Medicines Agency also granted the ADC a priority medicines designation.
"If it were to get approved at some point, it would certainly be an attractive option for patients with relapsed large cell lymphoma who are in palliative mode, and [are unable to be treated] with curative intent anymore," Kahl said.The novel pyrrolobenzodiazepine-based ADC ADCT-402 (Ioncastuximab tesirine; Lonca-T) is currently being evaluated in patients with relapsed/refractory B-cell lineage non-Hodgkin lymphoma (NCT02669017).
"This is an ADC that was interesting because of the payload that it uses. It is an antibody that targets CD19. It has its linker, but the payload in this case is this p-phenylenediamine (PPD) dimer, which is a highly potent cytotoxic agent," explained Kahl. "The company feels that because they used a stochastic conjugation technology, that they can more tightly control the number of payload molecules per antibody, which can result better pharmacokinetic properties and a better safety profile."
Treatment-related adverse events that were observed in the phase I dose-escalation study of ADCT-402 include skin-related changes, fatigue, nausea, increased gamma-glutamyl transferase (GGT), anemia, and peripheral edema.
A CD25 monoclonal antibody protease cleavable linker PPD dimer ADCT-301 is being investigated in an ongoing phase I/II trial in Hodgkin lymphoma and non-Hodgkin lymphoma (NCT02432235). Preliminary data reported that the overall response rate observed with this agent in Hodgkin lymphoma was 71% (n = 35) and 33% (n = 12) in patients with peripheral T-cell lymphoma. The toxicities observed so far are rash, edema, and GGT elevation. In this study 2 cases of Guillain-Barre syndrome were observed.
Additional novel ADCs under investigation include A-dmDT390-bisFv(UCHT1), known by the trade name Resimmune, coltuximab ravtansine (SAR3419), denintuzumab mafodotin (SGN-CD19A), pinatuzumab vedotin, moxetumomab pasudotox, and naratuximab emtansine (IMGN529).
"There are a lot of considerations that go into making an ADC, and the linker technology and the conjugation strategy just may turn out to be the most important part of all of this to optimize the therapeutic index for ADCs," concluded Kahl.
Kahl B. New antibody-drug conjugates. In: Proceedings from the 2018 Pan Pacific Lymphoma Conference; July 16-20, 2018; Maui, Hawaii.