Elsevier

Cancer Treatment Reviews

Volume 65, April 2018, Pages 87-95
Cancer Treatment Reviews

New Drugs
Bispecific antibodies in haematological malignancies

https://doi.org/10.1016/j.ctrv.2018.04.002Get rights and content

Highlights

  • BsABs and CAR T-cells are the most powerful tools for redirected T-cell therapy.

  • BsABs work independent from costimulatory molecules and major-histocompatibility complex.

  • Blinatumomab is the first approved bsAB in a haematologic neoplasia.

Abstract

Bispecific antibodies (bsAbs) combine the binding sites of two monoclonal antibodies in one molecule. The close proximity of a tumor specific antigen and an effector cell antigen results in a targeted activation of effector cells. The mechanism is similar to the chimeric antigen receptor (CAR) T-cells, recently approved in two haematologic cancers. CAR T-cells and bsAb represent the most powerful tools for major-histocompatibility complex (MHC) independent T-cell immune response against cancer. In contrast to CAR T-cells, bsAbs are “off the shelf” drugs. As a drawback, the efficacy is dependent on a prolonged application. More than 40 years of intensive research generate a plethora of bispecific constructs with a remarkable difference in manufacturability, stability, half-life time and receptor affinity. Blinatumomab was the first approved bsAb in relapsed and refractory acute lymphoblastic leukemia. By the mature experience of blinatumomab in more than 10 clinical trials over more than one decade, we learned some lessons on how to use this new principle. The efficacy is higher in patients with less tumor burden, suggesting the use as consolidation more than for initial debulking. Main resistance mechanisms are extramedullary relapses and the expression of the inhibitory PD-L1 molecule, suggesting the value of combination with checkpoint inhibitors. CD19 loss is infrequent after blinatumomab, preserving the option for alternative CD19-direct treatments. New bsAbs in lymphoma, myeloma and acute myeloid leukemia enter phase-I trials, together with many new constructs in solid cancer.

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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