The Modern Age of Monoclonal Antibodies: The Revolution of Daratumumab

*Gianfranco Lapietra, Francesca Fazio and Maria Teresa Petrucci*

## **Abstract**

CD38 is a transmembrane glycoprotein expressed on the surface of different cell lines with several functions (receptor, adhesion molecule, ectoenzyme). Based on its high expression in multiple myeloma cells, CD38 is one of the main molecules used in the target therapy age. Daratumumab is the first fully human monoclonal antibody tested in clinical trials, showing efficacy in relapsed/refractory multiple myeloma patients, especially in combination with immunomodulants and/or proteasome inhibitors. The synergic effect concerns multiple myeloma cells as well as the microenvironment (NK cells, macrophage, regulatory B/T cells and CD8+ effector cells). Therefore, the anti-multiple myeloma activity of Daratumumab greatly depends on the immune system: this is the reason why several ongoing clinical trial are testing its efficacy in the naïve patients, with a more effective immune system.

**Keywords:** daratumumab, monoclonal antibody, anti-CD38, multiple myeloma

### **1. Introduction: mechanism of action**

Daratumumab is the first fully IgG1K-human monoclonal antibody targeting CD38.CD38, also known as cyclic ADP ribose hydrolase, is a transmembrane glycoprotein expressed on the surface of hematopoietic and non-hematopoietic cell lines.

This protein plays different functions, both on the external and on the inner surface of cells. As a receptor, it takes part into the inflammatory response, stimulating the production of a great variety of cytokines through the interaction with CD31, on the surface of T cells. As enzyme, it is involved in the metabolism of nicotinamide adenine dinucleotide (NAD+), leading to the synthesis of cyclic ADP ribose (cADPR) which regulates cellular calcium trafficking [1].

In the context of bone niche, CD38 expression is very high on the surface of plasma cells. Pioneering studies have shown that this glycoprotein plays a key-role in the oncogenesis of multiple myeloma: increased intracellular levels of NAD+ seem to be associated with a less susceptibility to apoptosis [2] and the synthesis of cADPR favours the escape of tumour cells from the immune system [3]. In vitro, CD38 seems also to be associated with the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival [4].

**Figure 1.**

*Mechanism of action of daratumumab. Daratumumab binds CD38, killing myeloma cells via Fc-dependent immune effector mechanisms: CDC, ADCC and ADCP. Daratumumab also inhibits enzymatic activity of CD38, downregulating intracellular Ca2+ trafficking.*

Daratumumab binds CD38, killing tumour cells via Fc-dependent immune effector mechanisms including complement-dependent cytotoxicity (CDC), antibodydependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [5]. The complement activation seems to be the most effective mechanism used by Daratumumab [6]: the Fc tail of the drug binds the activating factor C1q leading both to ultimate activation of membrane attack complex and to deposition of C3b on the surface of multiple myeloma plasma cells. The activation of membrane attack complex causes osmotic lysis of cells while the deposition of complement factors attracts phagocytic cells. The recruitment of immune effector cells is also boosted by the release of circulating factors such as C3 and C5a (**Figure 1**).

The anti-tumour activity of Daratumumab does not depend only on the direct action on plasma cells but also on the interaction with other lymphoid and myeloid cells with a weak expression of CD38: NK cells, B and T regulatory cells and CD8+ effector cells. Krejcik et al. have demonstrated that bone marrow and peripheral blood from patients on treatment with Daratumumab present low levels of regulatory cells and high levels of NK and CD8+ effector cells. This monoclonal antibody may interfere with the immunosuppressive microenvironment in the multiple myeloma bone niche, in favour of major susceptibility for the plasma cells to the NK and CD8+ cells toxicity [7].

#### **2. Pharmacokinetics**

Daratumumab is usually administered at the dosage of 16 mg/kg weekly for 8 weeks then every 2 weeks for 16 weeks and every 4 weeks thereafter until progression of disease. The administration on a mg/kg basis is due to the observation that distribution and clearance of daratumumab depends on bodyweight. It seems to be not influenced by age, gender, race, mild renal and liver impairment. To our knowledge, the extra-liver metabolism of daratumumab is the reason for the absence of interactions with other drugs.

The efficacy and safety of this schedule have been demonstrated by two studies involving patients with relapsed/refractory multiple myeloma (RRMM) treated with the anti-CD38 monoclonal antibody as single agent: GEN501 and SIRIUS.

GEN501 was a phase I/II, open-label, multicenter study. In the dose-escalation part, sequential cohorts of patients received intravenous doses of daratumumab ranging from 0.005 to 24 mg/kg, administered over 6–8 h. In the dose-expansion

**69**

*The Modern Age of Monoclonal Antibodies: The Revolution of Daratumumab*

for 16 weeks, and every 4 weeks until disease progression [8].

of this formulation by the regulatory bodies is on the agenda.

ened and improved in patients continuing daratumumab.

combination with other agents (**Table 1a**).

**3. Daratumumab in relapsed/refractory multiple myeloma**

Approval of daratumumab by regulatory bodies was made possible thanks to clinical trials evaluating its use in RRMM. Patients with RRMM still represent the patients best benefitting from this monoclonal antibody, both as single agent and in

GEN501 and SIRIUS are the two main trials who led to approval of monotherapy with daratumumab. Both studies enrolled patients with RRMM: patients in GEN501 had relapsed after or were refractory to ≥2 prior lines of therapy, including inhibitors of proteasome (PIs), immunomodulatory drugs (IMiDs), chemotherapy and autologous stem cell transplantation (ASCT); patients in SIRIUS had relapsed after ≥3 lines of therapy, including a PI and a IMiDs or were double refractory to the most recently received PI and IMiDs. The primary endpoint of GEN501 was evaluation of safety while SIRIUS was designed to first evaluate overall response rate (ORR). Data regarding 148 patients from pooled analysis of the two trials confirmed how daratumumab, at the dosage of 16 mg/kg, is effective and safe in a population of heavily pretreated patients [12]. With a median number of 12 infusions, the ORR was 31.1%. At the time of the analysis, after a median follow-up of 20.7 months, the progression free survival (PFS) was 4 months, with a 12-month PFS rate of 22%. Stratifying the patients by the response according to International Myeloma Working Group, the PFS and the overall survival (OS) went out to be 15 months and not reached respectively for responders, 3 months and 18.5 months for patients with a stable disease or minimal response, 0.9 months and 3.7 months for non-responders. The median duration of response was 7.6 months and it deep-

**3.1 Daratumumab in relapsed/refractory multiple myeloma as single agent**

study, in three of the enrolled cohorts, daratumumab was administered based on the findings from the previous part at 8 mg/kg weekly for 8 weeks, every 2 weeks

SIRIUS was a phase II study with two parts. In the first part, the patients were randomized to receive daratumumab 8 mg/kg every 4 weeks or 16 mg/kg weekly for 8 weeks, then every 2 weeks for 16 weeks and every 4 weeks thereafter. In the second part, all patients received daratumumab 16 mg/kg, according to the findings

Intravenous administration of Daratumumab is associated with several side effects, included infusion-related reactions (see below). Therefore, this formulation requires a very slow infusion rate which may represent a disadvantage for the patient. Sever trials are evaluating the subcutaneous administration as an alternative. In the phase 1b PAVO study, the subcutaneous formulation of the monoclonal antibody was administered in patients with RRMM in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) to depolymerize hyaluronan in the subcutaneous space and increase the absorption rate [10]. This formulation at the dosage of 1800 mg was well tolerated and allowed to obtain similar concentrations and responses to the intravenous administration. Non-inferiority of subcutaneous daratumumab to intravenous formulation has been confirmed by preliminary results of the ongoing phase III trial COLUMBA [11]: enrolled patients with RRMM are randomized to receive either intravenous daratumumab 16 mg/kg or subcutaneous daratumumab 1800 mg. According to these studies, the approval

*DOI: http://dx.doi.org/10.5772/intechopen.95406*

from the first part [9].

#### *The Modern Age of Monoclonal Antibodies: The Revolution of Daratumumab DOI: http://dx.doi.org/10.5772/intechopen.95406*

study, in three of the enrolled cohorts, daratumumab was administered based on the findings from the previous part at 8 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression [8].

SIRIUS was a phase II study with two parts. In the first part, the patients were randomized to receive daratumumab 8 mg/kg every 4 weeks or 16 mg/kg weekly for 8 weeks, then every 2 weeks for 16 weeks and every 4 weeks thereafter. In the second part, all patients received daratumumab 16 mg/kg, according to the findings from the first part [9].

Intravenous administration of Daratumumab is associated with several side effects, included infusion-related reactions (see below). Therefore, this formulation requires a very slow infusion rate which may represent a disadvantage for the patient. Sever trials are evaluating the subcutaneous administration as an alternative. In the phase 1b PAVO study, the subcutaneous formulation of the monoclonal antibody was administered in patients with RRMM in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) to depolymerize hyaluronan in the subcutaneous space and increase the absorption rate [10]. This formulation at the dosage of 1800 mg was well tolerated and allowed to obtain similar concentrations and responses to the intravenous administration. Non-inferiority of subcutaneous daratumumab to intravenous formulation has been confirmed by preliminary results of the ongoing phase III trial COLUMBA [11]: enrolled patients with RRMM are randomized to receive either intravenous daratumumab 16 mg/kg or subcutaneous daratumumab 1800 mg. According to these studies, the approval of this formulation by the regulatory bodies is on the agenda.
