New DrugsBispecific antibodies in haematological malignancies
Section snippets
Historical perspective
In the early 60s, Alfred Nisonoff – a pioneer in antibody engineering – worked, for the first time, on the idea of “preparing antibodies of mixed specifity” [1]. However, it took more than 20 years, along with the introduction of the hybridoma technique, to establish the first monoclonal bsAb, enabling T-cell recruitment by Staerz and Bevan in 1985 [2]. This discovery was the origin of a rapidly growing interest in these technologies, between 1985 and 1995, called the “bispecific explosion” [3]
Terminology
More than 30 years of development result in a pronounced diversity of different bispecific molecules in clinical and preclinical trials. In a recent review, there is an overview about the “zoo” of more than 100 bispecific constructs [12], [13], [14]. Most of them combine two or more variable regions of monoclonal antibodies in complexly engineered molecules - with differences in size, half-life, stability and receptor affinity. The first generation of bsAbs was chemically coupled. Most of the
Blinatumomab
Blinatumomab is the first FDA and EMA approved bispecific construct for the treatment of relapsed and refractory (r/r) ALL. It is a small (55 kDa) single chain peptide connecting two variable antibody fragments directed against CD3 and CD19 [10]. Blinatumomab induces the formation of a cytolytic synapsis and activates T-cells without costimulatory molecules. There is a continuous recharging of granzymes resulting in a continuous attack of tumor cells without anergy or T-cell apoptosis [17].
Blinatumomab in ALL
In ALL, several phase-II trials were realized in the setting of minimal residual disease positive (MRD+) ALL [18], [19], in refractory and relapsed (r/r) Philadelphia (Ph) negative ALL [20], [21], in refractory and relapsed Philadelphia positive (Ph+) ALL [22] and in pediatric ALL [23]. At the time of this review, blinatumomab is approved in r/r Ph-negative ALL (FDA and EMA), in Ph+ ALL (FDA) and in pediatric ALL (FDA). Additionally, there is a randomized phase-III trial in ALL comparing
Blinatumomab in Non-Hodgkin lymphoma
In Non-Hodgkin lymphoma (NHL), several dosages and dose steps were evaluated in a multi-cohort phase-I trial [28]. This trial included seven dose levels (range form 0.5–90 µg/m2/day) as continuous intravenous infusion over 4 or 8 weeks using an implanted port and an ambulatory pump. 60 µg/m2/day was established as the maximum tolerated dosage. To avoid treatment discontinuation due to side effects, a stepwise dose escalation beginning with 5 µg/m2/day (flat dose 9 µg/day in subsequent trials)
Neurotoxicity and cytokine release syndrome
Administration of blinatumomab is frequently associated with adverse events, leading to permanent discontinuation in a significant proportion of patients. The most relevant side effects are neurotoxicity and cytokine release syndrome (CRS).
The mechanism of neurological toxicity of blinatumomab is not well understood. However, neurotoxicity occurs in trials with alternative CD19-bsAbs and with CD19 directed CAR T-cells. The extent of neurologic events in blinatumomab is dose-dependent;
Mechanisms of resistance in blinatumomab
In the first phase-II study in r/r ALL, three out of 10 relapsed patients had a secondary loss of CD19 and additional three patients had an extramedullary involvement [20]. With increasing data on relapsed patients, the secondary CD19 loss seems to be a rare event, between 3% and 8% of all relapsed patients [32], [33]. In CAR T-cells therapies, the incidence of CD19 loss is obviously higher (review by [34]). The CD19 loss in blinatumomab is often an isolated event without changing the biology
New constructs in NHL: CD19 and CD20
Based on the success of blinatumomab and CD19 directed CAR T-cells, alternative CD19 × CD3 antibodies have been developed with improved half-life and receptor affinity (overview in Table 1). AFM11 [43] is a bispecific but tetravalent construct (TandAb™), which has a half-life of 20 h. An additional advantage may be a higher CD3 affinity providing a lower effector to target ratio. AFM11 entered a phase-I program in lymphoma (NCT02106091) and ALL (NCT02848911).
Duvortuxizumab (MGD011) is a
New constructs in multiple myeloma
Since precursors of Multiple Myeloma (MM) have a B-cell origin, CD19-directed constructs like blinatumomab (NCT03173430) and even CD20-directed constructs (NCT00938626) are under clinical investigation. There is already a case report of a patient with coexistent MM and ALL who achieved a very good partial response (VGPR) of MM to blinatumomab, actually initiated for ALL treatment [56].
The B-cell maturation antigen (BCMA) is an attractive target in MM, since it is more selectively expressed on
New constructs in acute myeloid leukemia
In acute myeloid leukemia (AML), several bsAbs have been developed (review by [63]). Potential targets are CD33, CD123, CLL1, CD45, CD46 and Anti-IL1RAP. Since neither of these targets are highly selective to leukemic cells, potential side effects like cytokine release syndrome are possible. The FDA placed a temporary hold on two of three ongoing clinical trials due to adverse effects.
The CD33 antigen was one of the first targets, which was therapeutically addressed by monoclonal antibodies.
New constructs in Hodgkin lymphoma
In Hodgkin lymphoma, bispecific CD30 antibodies have a long history. In contrast to B-cell malignancies, antibody constructs activate compounds of the innate immune system [65]. The first CD30 × CD16 antibody was tested in patients in the late 90s with a moderate response rate (1 CR and 1 PR in out of 15 patients) [6]. In 2001, a bispecific CD30 × CD64 (recruiting monocytes and macrophages) showed one CR and four PRs in 10 patients without severe side effects [66]. Despite these early
New developments
In contrast to the “living” and self-expanding CAR T-cells, bsAbs have the handicap of short persistence in the patient and the low target to effector ratio in heavily immunosuppressed patients. A merging of both principles may be the modification of immune or tumor cells to permanently express bispecific molecules [68]. There are at least four concepts, which are under preclinical evaluation: (a) modified oncolytic viruses, (b). transfected T-cells, (c) transfected mesenchymal stem cells (MSC)
Future directions
Effective targeting of cancer cells, selection of the optimal tumor antigen, stimulation of effector cells without an overshooting immune response, overcoming the immunosuppressive environment, stability and comfortable application is still challenging after more than 40 years of research and development in bsAbs. With the first approvals of CAR T-cells [78], [79], [80], [81], [82], the contest of the best way of targeted immunotherapy is still open. Looking to the available response data of
Acknowledgement
A special thank belongs to Michéle Zimmerman for the thorough reading and correction of the manuscript.
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