Journal of Oncology Research Reviews & Reports

Introduction

Multiple myeloma (MM), as defined by a clonal plasma cell proliferation, manifests as end organ damage caused by the abnormally high monoclonal paraprotein. MM forms a part of the spectrum of monoclonal gammopathy. 1.8% of all new cancer cases in the United Stated are contributed by MM. Geriatric population is the most affected by MM with a median age of diagnosis as 65 years [1]. It is expected that in 20 years the number of cases diagnosed annually will almost double. It is twice as common in African Americans than Caucasians and male-to-female ratio is 3 to 2 [2]. The survival outlook for multiple myeloma is changing sequentially as its treatment evolves. Most profound impact has been reported with the use of proteasome inhibitors and immunomodulatory drugs. Recently, monoclonal antibodies have been approved for the treatment of multiple myeloma. Survival has also been reported to improve with the ancillary care for bone disease related to myeloma and other interventions. Median overall survival has improved from one to two years to seven to eight years. Also, the patients experience a better quality of life and long-term survival. Five-year survival has risen to 45% in 2007 which previously used to be 30% in 1990 [3,4]. With the development of these newer therapies, there has been a possibility of deep responses such as minimal residual disease-negative state. More than 12,000 patients die annually out of the 30,000 new cases of MM [5]. The age-adjusted incidence in the United States has remained 4 per 100,000 annually for decades [6].

In order to diagnose there must be ≥10% clonal bone marrow plasma cells or plasmacytoma proven on biopsy with one or more multiple myeloma defining events (MDE) such as CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions), ≥60% bone marrow clonal plasmacytosis, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging. The treatment of MM becomes problematic because of this genetic complexity. As yet MM is primarily treated with chemotherapies in combination with proteasome inhibitors, anti-resorptive agents such as bisphosphonates, corticosteroids and bone marrow transplantation.

Bispecific antibodies (BsAbs) offer a promising immunotherapeutic approach for various malignancies including MM.
In this article, we review the potential benefits of BsAbs in MM patients. In addition, new BsAbs developments and clinical trials for various MM targets are discussed in detail. Finally, we discuss the use of BsAbs as the future treatment of MM as well as the obstacles that need to be overcome.

What are Bispecific Antibodies

Bispecific antibodies-are types of antibodies that have two different antigen binding sites in one molecule. With the help of hybridoma technology first monoclonal BsAbs were produced in the 1980s. Although it was first described in the 1960s, the first article mentioning its therapeutic use was published in 1992. Due to its therapeutic use, it has gained interest in the scientific community and no publications on this topic have increased significantly. Monoclonal antibodies are derived from a one parent cell which are identical immune cells. They bind to the same epitope which is Abs’ binding site on the antigen. We are focusing on the development of Abs that can not only bind two or more antigens but also conjugate to chemo and radiotherapy agents.

BsAbs are being developed that has 2 antigen binding sites in which one binds to CD3 receptor that is responsible for activating cytotoxic T lymphocytes and other site binds to antigen specific to tumor cells e.g., CD19, CD20, Epithelial cell adhesion molecules [ EpCAM], CEA etc [7]. Thus, BsAbs help activate cytotoxic T lymphocytes against the antigen specific to tumor cells and promotes the destruction of tumor cells. These antibodies are not only directed against the tumor cells but are also being studied for the treatment of other diseases.

Advantages of Bispecific Antibodies

In contrast to monospecific antibodies, bio specific antibodies have several advantages.
1. BsAbs have greater binding specificity compared to monospecific antibodies because they interact with two different surface antigens.
2. They are responsible for activating specific effector cells of the immune system like cytotoxic T cells which helps in more robust killing of the target.
3. They can also be conjugated to chemo-radio agents.
4. They are cheaper compared to two monospecific drugs used for the treatment of one disease.
5. Importantly, modulator of one disease may play an important role in modulation/co-expression of receptors involved in other diseases, thus targeting two different growth promoting receptors on a single tumor not only increases the antitumor effect of the drug but also suppresses the development of the resistance [8,9].

These antibodies are being studied as potential treatments for different diseases including cancer, autoimmune diseases, bleeding disorders, chronic inflammatory diseases and infections.

T cells are key mediators of the adaptive immune system which enhance the destruction of cancerous cells via different mechanisms [10]. These mechanisms include; recognizing and attacking infected host cells, increasing the production of cytokines and regulating the immune response. Due to these factors T cells are being considered for the treatment of patients suffering from MM. In 2009, European Union clinically approved Catumaxomab (anti-EpCAM x anti-CD3), the first BsAb. This was followed by approval of BaAb, Blinatumomab (anti-CD19 x anti-CD3) by FDA in 2014 [11-13]. Since then a lot of research and clinical trials have been done on a variety of BsAb. Among these, BsAbemicizumab has been approved by the FDA for the treatment of hemophilia A [14,15]. However, despite 13 BsAb in clinical trials, no medicine has been approved for the treatment of MM as of now. In 2017, a clinical study was started to observe the effects of BsAb-blinatumomab in relapsed/refractory MM patients.

Types of Bispecific Antibodies

There are 100 different classes of BsAb and all these can be divided into 2 main categories based on their fragments i.e. crystallizable (fc) region and antigen binding (fab) variable region. BsAb under both these categories are under trials for MM. The Fc domain BsAb can be further classified into 2 categories based on the presence and absence of the Fc segment.
The presence of the Fc domain allows BsAb to be more stable, prolonging its half life in vivo [16]. It induces the migration of natural killer cells at the site of tumor cells by activation dependent cell mediated cytotoxicity (AACD). At the same time it stimulates the complement mediated cytotoxicity by fixing the complement. Currently a large number of BsAb are being produced by recombinant DNA technology, although clinical trials were initially run to generate them by chemically combining 2 monoclonal ab.

Among many molecules expressed by MM cells on their surfaces, B-cell Maturation Antigen (BCMA) happens to be the most recognized antigen; clinicals trials directed to generate antibodies against it seem most promising[17,18]. This is due to the fact that BCMA is expressed by the neoplastic cells in large amounts and the only other cells in the body which normally produce it in negligible amounts are pDC [19-21]. Thus making it the best target for any therapeutic measures taken towards MM. So far CAR and ADC happen to be T- cell mediated BCMA directed interventions directed against MM other than BsAb.

Currently, no further studies are evaluating AMG 420 based on the pharmacokinetics mentioned earlier. However, a study evaluating AMG 701, an extended half-life BiTE without the need for continuous infusion, is in progress [22].

A humanized Ig-like BiAb pf-06863135 (PF-3135) is currently undergoing a dose-escalation study in RRMM patients with one infusion weekly, and the results of the first 17 patients have been reported. The clinical benefit rate (defined as best response > stable disease) is 41 %, and dose intensification is still ongoing. One patient showed a minimal response (6%), three patients had G > 3 AEs, and one patient had non-hematologic AE with increased blood liver enzymes (LFT).

Another Ig-like BiAb CC-93269 that asymmetrically targets BCMA via two binding sites and CD3 via one binding site is currently being studied in heavily pre-treated RRMM patients in phase-1 dose-escalation trial with the results of the first 30 patients already been reported. It is given intravenously over 2Hr; weekly in cycles 1-3, on alternative weeks in cycles of 4-6, and every 28 days after that. The ORR was 43% throughout the dose cohort approaching 89%, with the highest tested dose of 10mg; thus, it became dose-dependent. A milder CRS was frequently observed (all grades 77%; G >3 4%), neutropenia (G >3 43% and infections (G>3 30%) being other main toxicities. Thus, Dexamethasone prophylaxis was given to all patients treated with doses > 6mg.

Teclistamab is another Ig-like BiAb, studied in RRMM patients in a phase-1 dose-escalation trial with the results of the first 78 patients already being reported. Priming doses followed by weekly infusions are given at different dose levels (0.3-720 mcg/Kg). The ORR (overall response rate) is 67% in 12 patients treated with the highest dose (270mcg/Kg), while no efficacy data is available for the 720mcg/kg dose cohort. CRS was commonly observed (56%), mostly G1 or 2, and Neurotoxicity was reported in 8% of patients.
Several studies have reported the expression of CD19 by MM stem cells, and clinical studies are in progress to evaluate the antimyeloma activity of Blinatumomab in humans. A phase 1 clinical study (NCT03173430) is in progress to determine the feasibility, safety, and antimyeloma activity of Blinatumomab post-Autologous HSCT. Blinatumomab is administered after high-dose Melphalan and Autologous stem cell transplant.

The patient, a 70-year old female, in partial remission with Lenalidomide therapy for MM, developed pre-B-ALL, underwent cytoreductive treatment, and started on Blinatumomab induction therapy, resulting in complete remission of her ALL and a good partial response to MM as per the International Myeloma Working Group criteria [23]. Although this patient had an atypical MM tumor with CD19 positive staining MM cells, it provides promising results of antimyeloma activity of Blinatumomab [23].
The primary targets for MM are BCMA, Syndecan-1 (CD-138), the target of Wue- 1 mAb, and Fc receptor-like 5 (Fcrl5 or FcHR5) [24-28]. Multiple Myeloma is largely an incurable disease with relapse and development of PI- and or IMiD-resistance. Thus, the management of late-stage relapsed/refractory RRMM, especially, is challenging in clinical practice.The Trials of use of bispecific antibodies in MM are shown in the Table 1.

Table 1: The Trials in literature mentioning the use of bispecific antibodies in multiple myeloma (MM)

Limitations

Most of the studies included in our review are either ongoing clinical trials or to be conducted in future and have not arrived at a definite conclusion yet. Also, there were not enough clinical trials to determine the role and efficacy of bispecific antibodies in treatment of multiple myeloma. Our review will hopefully have potential benefits for future researchers for carrying out further studies regarding this topic.

Conclusion

With several benefits of bispecific antibodies compared to other therapies, they are being studied for their use in various diseases like cancer, autoimmune, infectious disease etc. BsAb PF-3135 has shown to be beneficial in an ongoing study with some adverse effects reported in few patients. Other BsAb like CC-93269 acting via BCMA and CD3 antagonism and teclistamab are also being studied. Blinatumab has also shown promising antimyeloma activity. However, the studies on these agents are in initial phases. These agents have exhibited promising efficacy in preclinical and early clinical studies in MM, specifically the anti-BCMA Abs seem to be promising in RRMM [29].
Despite some studies showing adverse effects like CRS and development of HAMA associated with use of BsAb, development of these new treatments is going to greatly contribute to improve outcomes for a wide group of patients which also requires further clinical studies to be conducted with focus on demonstration of efficacy and safety profile.

Acknowledgement: Arslan Inayat MD; University of Buffalo for organizing the whole project.

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