Bispecific Antibodies: The Next Generation of Immunotherapy
Advances in biotechnology have improved the production and recombination of antibodies, leading to improvements in monoclonal antibody therapies.
The use of immunotherapy to kill cancer cells was proposed many decades ago but has only recently been realized as a revolutionary treatment.1 Monoclonal antibodies, or mAbs, have evolved into a standard of cancer care over the past 20 years, but the quest for better mAbs continues.2
Advances in biotechnology have improved the production and recombination of antibodies, leading to improvements in mAb therapies.3 One promising approach to improving mAbs, specificity for tumor cells, is through the dual binding mechanism of bispecific antibodies (bsAbs). Unlike conventional mAbs, which have both binding sites directed to the same target, bsAbs attach to 2 different antigens simultaneously. BsAbs used in oncology provide a higher binding specificity, which allows the immune system to directly contact tumor cells, enhancing their cytoxicity.4 In the past 10 years, the amount of research devoted to bsAbs has increased significantly.4 The majority of oncologyrelated bsAbs in clinical development engage immune cells to destroy tumor cells; however, bsAbs can also be used to block tumor signaling pathways or deliver cytotoxic payloads to tumors.3
BsAbs build upon the fundamental components found in antibodies, like human immunoglobulin (IgG), to generate new combinations and functionality.5 The basic structure of IgG consists of 2 light-chain (LC) and 2 heavy-chain (HC) units that form a Y-shaped protein structure. The IgG antibody binds to specific antigens, like the CD19 marker, through the fragment antigen-binding region and to the host immune cells though the fragment crystallizable (Fc) region.5
There are several ways to generate bsAbs using variations on the baseline HCs and LCs. In recent years, genetic engineering has increasingly been used to produce a variety of antibodies for greater flexibility in size, valence, specificity, half-life, and biodistribution.1 BsAbs can be broadly categorized into 2 main groups: bsAbs that contain the Fc region (similar to IgG), and bsAbs that lack the Fc region.4
BsAbs that have the Fc region intact are more stable but can result in greater toxicities by nonspecifically activating T cells.5 BsAbs that lack the Fc region are smaller and less stable with a shorter half-life, but they can potentially penetrate the tumor cell more effectively.1 Because of the short half-life, a continuous infusion for administration is often required.5
Although there are several types of bsAbs, the most common are classified as trispecific antibodies and bispecific T-cell engagers (BiTEs).4 The only bsAb in the field of oncology that is FDA approved at the time of this publication is blinatumomab (Blincyto; Amgen).
Blinatumomab is a BiTE that consists of 2 variable segments, one binding to B-lymphocyte antigen CD19 and the other to CD3 on T cells.4 It is indicated to treat adults and children with B-cell acute lymphoblastic leukemia (B-ALL) in first or second complete remission with minimal residual disease or relapsed/refractory (R/R) B-ALL. In studies, blinatumomab demonstrated a remarkable 43% complete remission versus 20% for standard-of-care chemotherapy in patients with R/R B-ALL, results that helped spur further bsAb development.5
Blinatumomab currently shares space in the National Comprehensive Cancer Network guidelines for ALL with traditional chemotherapy; chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel (Kymriah; Novartis); inotuzumab ozogamicin (Besponsa; Pfizer), a humanized antiCD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin; and selected tyrosine kinase inhibitors, such as dasatinib (Sprycel; Bristol Myers Squibb) and ponatinib (Iclusig; Takeda).6,7 Selection of blinatumomab largely depends on availability of treatment centers that have expertise with and access to this agent, along with the resources to manage potentially severe adverse effects (AEs), such as cytokine release syndrome. Treatment expense is also a key consideration, as blinatumomab therapy can be expensive, with estimated treatment costs over $500,000 per year.8 However, blinatumomab costs are comparable to both CAR T-cell and inotuzumab ozogamicin therapies for ALL.
One important consideration is the potential for malignant cells to downregulate or lose expression of CD19 or CD22, the targets of blinatumomab and inotuzumab ozogamicin respectively, leading to further relapses.9 Blinatumomab is currently being studied in additional clinical trials that may help clarify its most effective place in B-ALL therapy.8 Additionally, blinatumomab has received orphan drug designation for acute and chronic lymphocytic leukemia, hairy cell leukemia, indolent B-cell lymphoma, and prolymphocytic leukemia.
The pipeline for bsAbs is active. According to an article by Labrijn and colleagues published in August 2019, at least 85 known bsAbs are in clinical development, with approximately 86% of them being evaluated for the treatment of cancers.9 BsAb trial initiation has increased over the 5-year period from 2014 to 2018. Additionally, researchers have transitioned toward investigating bsAbs as cancer treatments, with less emphasis on other indications in recent years. By year of clinical trial initiation, oncology-related indications account for 46 of the 48 bsAb trials that began in 2017 and 2018 [TABLE 1].9
Many of the bsAbs in development are in earlier stages of clinical trials. By narrowing the focus to oncology-related bsAbs that are potentially close to completing regulatory filing for possible FDA approval, 4 products appear promising. These agents have either advanced to phase 3 clinical trials or have been identified as receiving breakthrough designation from the FDA. Products with a breakthrough designation are included in TABLE 2, as they have the potential to be approved based on the efficacy and safety results of early-phase trials (ie, phase 1 or 2).
Earlier this year, Roche announced plans to commence a study this fall using glofitamab in combination with gemcitabine and oxaliplatin plus obinutuzumab pretreatment in patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBL).10 Non-Hodgkin lymphomas, such as DLBL, can represent substantial treatment challenges, particularly with multiple relapses where prognosis is poor.11 The phase 3 study is expected to conclude in mid-2022.
In a phase 1 trial in heavily treated patients with a variety of non-Hodgkin lymphomas (NHLs), glofitamab was given for up to 12 cycles of 21 days each. End points evaluated included complete response (CR) and overall response rate (ORR). In patients receiving glofitamab greater than or equal to 0.6 mg (n = 146), ORR was achieved by 45.5% of patients with aggressive forms of NHL and 65.2% of those with indolent NHL.11 Among these patients, CR was attained by 30.9% and 52.2% in aggressive and indolent NHL, respectively.11 For patients receiving glofitamab greater than 10 mg (n = 103) to treat aggressive NHL, ORR was 49.4% and CR was 34.1%.11 For individuals with indolent NHL, ORR was 66.7% with a CR rate of 50%.11 The most commonly reported AEs for patients receiving glofitamab greater than or equal to 0.6 mg were cytokine release syndrome (56.4%), neutropenia (30.8%), pyrexia (30.1%), anemia (22.4%), and thrombocytopenia (16.7%).11
MacroGenics’ MGD013 is a novel, dual-affinity retargeting antibody designed to provide coblockade of PD-1 and LAG3 in patients with gastric or gastroesophageal junction cancer (GC or GEJ)12 who have previously untreated locally advanced unresectable or metastatic HER2-positive GC or GEJ adenocarcinoma. The phase 2/3 MAHOGANY study will examine MGD013 in combination with margetuximab, an Fc-optimized mAb targeting HER2 for both cancers. MAHOGANY began September 2019 and is expected to conclude mid-2024 with final completion mid-2026.12
A separate phase 1, dose-escalation study included an arm evaluating MGD013 plus margetuximab for HER2-positive solid tumors, among other cancers. MGD013 was given up to 1200 mg every 2 weeks. ORR was achieved by 43% of patients at the data cutoff point for interim analysis (n = 205).13 AEs were described as “generally consistent with anti—PD-1 monotherapy.”13 AEs associated with these therapies are generally mild to moderate in terms of severity and most commonly affect the skin, colon, lungs, liver, and endocrine system.13
Janssen Pharmaceutical Companies’ amivantamab is being evaluated in the phase I CHRYSALIS trial as monotherapy and in combination with lazertinib, carboplatin, and pemetrexed for the treatment of advanced non—small cell lung cancer (NSCLC) that is metastatic or unresectable.14 Amivantamab is an anti—EGFR-MET bsAb targeting exon 20 mutations in NSCLC. CHRYSALIS is expected to conclude in mid-2021, with final completion scheduled for late 2022.14
Mosunetuzumab is a BiTE being studied for various types of leukemia and lymphoma in early-phase studies. In an open-label, multicenter phase 1 study involving patients with different subtypes of NHL who were relapsed or refractory to prior treatments, ORR was achieved by 43.8% of patients with 25% reaching a CR (n = 218). Further trial results are needed to get a clearer picture of this agent’s potential.15
BsAbs will occupy a growing role in oncology pharmacy practice for the foreseeable future and will continue driving innovative drug design and growth in oncology pharmacy. Health systems will need to be prepared to offer robust pharmacotherapy support for health care teams administering these agents. AE management and supportive care are key areas that oncology pharmacy practices will need to further expand to aid these treatment modalities.16
Oncology pharmacy specialists will need to take lead roles in developing policies and procedures surrounding the use of bsAbs in clinical practice.17,18 Cost considerations and accessibility will be key drivers of utilization and growth for these agents, as the current oncology landscape is moving toward highly efficacious immunotherapies.
BsAb-based therapies will continue to gain therapeutic space in the treatment of relapsed/refractory cancers, particularly those with targetable cellular markers or genomic susceptibilities. Interest in these agents remains strong, and the development pipeline has matured rapidly, with oncology bsAbs more than quadrupling since 2014.8,9
Overall, bsAbs appear primed to expand into new frontiers of oncology treatment, with the promise of next-generation immunotherapies that will expand treatment options for many difficult-to-treat hematologic malignancies and solid tumors.
RYAN CHANDANAIS, MS, CPHT, is an emerging therapeutics analyst at Optum Specialty PharmacyDANNY GAVORD is a PharmD candidate at Ferris State University in Big Rapids, MichiganMATTHEW MCTAGGART, PHARMD, is a PGY1 resident with Diplomat Specialty Pharmacy, Flint, Michigan.
- Chen S, Li J, Li Q, Wang Z. Bispecific antibodies in cancer immunotherapy. Hum Vaccin Immunother. 2016;12(10):2491-2500. doi:10.1080/21645515.2016.1187802
- Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15(6):361-370. doi:10.1038/nrc3930
- Suurs FV, Lub-de Hooge MN, de Vries EGE, de Groot DJA. A review of bispecific antibodies and antibody constructs in oncology and clinical challenges. Pharmacol Ther. 2019;201:103-119. doi:10.1016/j.pharmthera.2019.04.006
- Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018;12:195-208. doi:10.2147/DDDT.S151282
- Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review. Pharmacol Ther. 2018;185:122-134. doi:10.1016/j.pharmthera.2017.12.002
- NCCN. Clinical Practice Guidelines in Oncology. Pediatric acute lymphoblastic leukemia, version 2.2020. Accessed August 6, 2020. https://www.nccn.org/patients/guidelines/content/pdf/ped_all_patient.pdf
- NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 1.2020. January 15, 2020. Accessed August 7, 2020. https://www.nccn.org/patients/guidelines/content/pdf/ped_all_patient.pdf
- Drawdy L, Jones LA, Hall PD. Blinatumomab: A Step Forward in the Treatment of B-Cell Precursor Acute Lymphoblastic Leukemia. J Hematol Oncol Pharm. 2019;9(2):38-46
- Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18(8):585-608. doi:10.1038/s41573-019-0028-1
- A phase III study evaluating glofitamab in combination with gemcitabine + oxaliplatin vs rituximab in combination with gemcitabine + oxaliplatin in participants with relapsed/refractory diffuse large B-cell lymphoma. ClinicalTrials.gov. Updated October 13, 2020. Accessed October 13, 2020. http://clinicaltrials.gov/ct2/show/NCT04408638
- Roche presents updated data on novel CD20xCD3 bispecific antibody cancer immunotherapy glofitamab in people with heavily pre-treated non-Hodgkin lymphomas. News release. Roche. June 12, 2020. Accessed August 20, 2020. http://roche.com/investors/updates/inv-update-2020-06-12.htm
- Combination margetuximab, INCMGA00012, MGD013, and chemotherapy phase 2/3 trial in HER2+ gastric/GEJ cancer (MAHOGANY). ClinicalTrials.gov. Updated August 31, 2020. Accessed October 13, 2020. http://clinicaltrials.gov/ct2/show/NCT04082364
- MacroGenics announces preliminary clinical results from MGD013 and MGC018 to be presented at ASCO annual meeting. News release. MacroGenics Inc. May 13, 2020. Accessed August 20, 2020. http://ir.macrogenics.com/news-releases/news-release-details/macrogenics-announces-preliminary-clinical-results-mgd013-and
- Study of JNJ-61186372, a human bispecific EGFR and cMet antibody, in participants with advanced non-small cell lung cancer (CHRYSALIS). ClinicalTrials.gov. Updated October 9, 2020. Accessed October 13, 2020. https://clinicaltrials.gov/ct2/show/NCT02609776
- Schuster SJ, Bartlett NL, Assouline S, et al. Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-Cell (CAR-T) therapies, and is active in treatment through multiple lines. Blood. 2019:134(suppl 1):6. doi:10.1182/blood-2019-123742
- What are immunotherapy side effects? European Society for Medical Oncology. 2017. Accessed September 4, 2020. https://www.esmo.org/content/download/124130/2352601/file/ESMO-Patient-Guide-on-Immunotherapy-Side-Effects.pdf
- Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 Hematology/Oncology Pharmacist Association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
- Further defining the scope of hematology/oncology pharmacy practice. Hematology/Oncology Pharmacy Association. 2019. Accessed October 13, 2020. http://www.hoparx.org/images/hopa/resource-library/guidelines-standards/HOPA18_Scope-2_Web2.pdf