Bispecific Antibodies in Non-Hodgkin’s Lymphoma: History
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Hematology

Bispecific antibodies (bsAbs) are molecules that simultaneously bind two different antigens (Ags). Their development represents a very active field in tumor immunotherapy with more than one hundred molecules currently being tested. More specifically, bsAbs have elicited a great interest in the setting of non-Hodgkin’s lymphomas (NHLs), where they could represent a viable option for more fragile patients or those resistant to conventional therapies. This review will focus on those bsAbs currently in clinical use (Blinatumomab) or in clinical trials (Glofitamab, Mosunetuzumab, Odronextamab, Epcoritamab), with a brief overview of future directions.

  • bispecific antibody
  • non-Hodgkin’s lymphoma
  • Blinatumomab
  • Mosunetuzumab
  • Epcoritamab
  • Glofitamab
  • Odronextamab

1. Blinatumomab

Blinatumomab, an anti-CD19/CD3 bispecific T-cell engager (BiTE), was the first bsAb to show high efficacy in the relapsed/refractory (R/R) setting of B-cell acute lymphoblastic leukemia (B-ALL) and was approved by the Federal Drug Administration (FDA) for this indication in 2014[1][2]. In addition, it has also been assessed as a salvage strategy in R/R NHLs[3][4][5].
In a phase I study, Blinatumomab was used as a continuous infusion (for four to eight weeks, plus an additional four weeks if clinical benefit was achieved) with an escalated doses schedule. Seventy-six R/R B-NHLs (including 14 diffuse large B-cell lymphoma, DLBCL) were enrolled. Results showed that doses below 60 µg/m2/day were associated with poor response rates while a dose of 90 µg/m2/day was limited by neurotoxicity. In the extension phase, 11 patients with R/R DLBCL received the target dose with an overall response rate (ORR) of 55% and a complete remission (CR)/unconfirmed CR rate of 36%. With regards to adverse events (AEs), neurologic events occurred in 71% of patients with >20% of them reported grade 3, while no grade 4 or 5 events occurred[3].
Viardot et al. in a limited phase II study (21 evaluable patients) showed an ORR of 42% with a CR rate of 19%. Notably, grade 3 AEs were reported in 22 (95.7%) of patients with encephalopathy (9%) and aphasia (9%) being the most common neurologic ones. No patient had a grade 4 or grade 5 neurologic events and no cases of cytokine release syndrome (CRS) was reported[4].
Finally, a phase II study by Coyle et al. evaluated Blinatumomab as a second salvage in R/R DLBCL cases. In 41 patients, after 12 weeks of therapy, the ORR was 37% with a CR rate of 22%. A high rate of treatment discontinuation was reported, resulting in only 59% of patients receiving more than 80% of their intended dose[5].

2. Glofitamab

Glofitamab is a humanized mouse-derived IgG1-like T-cell engaging bsAb possessing a 2:1 structure with bivalency for CD20 (which improves affinity for CD20-expressing cells) and monovalency for CD3. The fragment crystallizable (Fc) structure is characterized by the absence of an Fc γ receptor and complement binding site, which influences its pharmacokinetic and pharmacodynamic properties. Bacac et al. in a preclinical study had shown its superior potency compared with other tested bsAbs[6], encouraging research in the field of bsAbs as a whole.
In a phase I/Ib trial Glofitamab was used as a single-agent in R/R B-NHLs. The monoclonal anti-CD20 Ab Obinutuzumab was administered before Glofitamab in order to prevent CRS by occupying surface CD20 Ags on lymphoma cells and depleting peripheral B-cells. Glofitamab was given as an intravenous infusion, in 14- or 21-day cycles for up to 12 cycles, and an escalating doses schedule of 0.6 to 25 mg was used. One hundred and seventy-one patients were enrolled with a median age of 64 years (range, 22–85). Aggressive NHLs (aNHLs) (DLBCL, transformed follicular lymphoma, tFL), primary mediastinal large B-cell lymphoma, PMBCL, mantle cell lymphoma, MCL, and Richter’s transformation) and indolent NHLs (iNHLs) (grade 1–3A FL) were enrolled; patients had a median of 3 prior lines of therapy (range, 1–13) and 90.6% were refractory to all prior therapy. Clinical activity was observed at all doses. Among patients with aNHLs, ORR and CR rates were 48.0% and 33.1% respectively, including 41.1% and 28.8% in patients with DLBCL and 55.2% and 34.5% in patients with tFL. In grade 1-3A FL, 70.5% achieved response with a high rate of CR (47.7%). In an aNHL setting, the median duration of response (DOR) was 5.5 months (95% CI, 4.4 to not estimable; range, 0.8–28.8 months) and the median progression free survival (PFS) was 2.9 months (95% CI, 2.1 to 3.9). In grade 1–3A FL, the median DOR was 10.8 months (95% CI, 3.8 to not estimable) and the median PFS was 11.8 months (95% CI, 6.3 to 24.2). AEs were reported in 98.2% of patients, with the most common being CRS, occurring in 50.3% of patients at grade 1 and in 1.2% at grade 4. Symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) during CRS were uncommon and all resolved within 3–72 hours. Incidence of CRS increased with dose but declined considerably after the first administration. Grade ≥ 3 neutropenia occurred in 25.1% of patients and infections and febrile neutropenia occurred in 51.5% and 2.9% of patients, respectively[7].
These pieces of data were confirmed by another trial. Interim data presented the results of 52 patients with R/R NHLs who received Glofitamab step-up dosing with Obinutuzumab pretreatment to reduce toxicity. Glofitamab was administered intravenously in a weekly step-up dosing regimen with a schedule of either 2.5/10/16 mg or 2.5/10/30 mg. Glofitamab was given every three weeks for up to 12 cycles. A total of 52 patients were treated in the two cohorts; these patients had a mean age of 68 years (range, 44–85) and 53.8% were male. More than half of the patients (53.8%) had aNHLs (DLBCL, tFL, Richter’s transformation, MCL), while 46.2% of patients had indolent grade 1-3A FL. Patients were highly pretreated (median of 3 lines of therapy consisting of chemoimmunotherapy, autologous stem cell transplantation in 21.2%, a PI3K inhibitor in 9.6%, chimeric antigen receptor, CAR, T-cell therapy in 5.8%, and cancer immunotherapy in 1.9%). The ORR was 63.5% for all patients with a complete metabolic response (CMR) observed in 53.8% patients. In those with iNHLs the ORR was 66.7% and the CMR rate was 54.2%, versus 60.7% and 53.6%, respectively, in the aNHLs group. CRs were generally achieved early and observed from the first or second response assessment. Almost all patients (98.1%) experienced at least 1 AE, and 88.5% had treatment-related events. No fatal AEs were reported. The most common AEs were CRS, neutropenia, pyrexia, and thrombocytopenia[8].
Several trials are still ongoing, and results are pending.

3. Mosunetuzumab

Mosunetuzumab is a fully humanized bispecific IgG1 monoclonal Ab, binding CD20 on tumor cells and CD3 on T-cells. It too has a modified Fc with no Fc γ receptor or complement binding site, and it presents only one binding site to CD20. It is currently under study as monotherapy or combined with other drugs to treat B-cell NHLs.
The phase I/Ib GO29781 study (NCT02500407) evaluated mosunetuzumab monotherapy in patients with NHLs R/R (aggressive and indolent forms) [45]. Mosunetuzumab was given with a step-up dose on days 1, 8, and 15 of cycle 1, followed by a fixed dose on day 1 of each subsequent cycle up to a maximum of 17 cycles. The schedule ranged from a weekly step-up dose of 0.4/1/2.8 to 1/2/40.5 mg. Two hundred and seventy patients were evaluated (66.7% had an aNHLs—including DLBCL, tfFL, and MCL—and 31.5% an iNHLs). Of note, patients were heavily pretreated and 11.1% had received prior CAR T-cell therapy. Efficacy analysis showed high response rates in both aNHLs and iNHLs. In fact, an ORR of 37.4% (CR 19.5%) and 62.7% (CR 43.3%) was reported in aNHLs and iNHLs, respectively [45]. In CAR T-cell R/R patients the ORR was 38.9% (CR rate of 22.2%) [45].
Similarly, high response rates were reported in the POD24 population [53]. In all groups, responses were durable over months with a median DOR of 20.4 months (95% CI: 9.4–22.7) [53]. AEs were reported in 60 pts (97%); 14 pts (23%) experienced CRS. CRS events were reversible, mostly of grade < 2 and predominantly occurred during the first cycle. No patient required tocilizumab, intensive care unit admission or use of vasopressors for CRS management. Neurologic AEs (NAEs) were observed in 28 pts (45%) with headache (24%), insomnia (15%), and dizziness (11%) the most reported. No grade ≥ 3 NAEs or serious NAEs were reported [53].
These safety data are confirmed in a heavily pre-treated, R/R CAR-T cell therapies population [45].
A subcutaneous (SC) monotherapy with mosunetuzumab was tested in study GO29781 (NCT02500407) to investigate alternative dosing strategies. R/R patients with aNHLs or iNHLs were included, and doses of 1.6 to 20 mg oce every three weeks were considered. High efficacy rates were reported, with an ORR of 86% and a CR rate of 29% in patients with iNHLs and 60% and 20% in patients with aNHLs, respectively [54]. All responses were durable with a median of 6.9 months [54]. The SC administration of mosunetuzumab has shown a low absorption rate and high bioavailability (>75%) confirming a favorable toxicity profile compared to the IV formulation (reduced rate of grade ≥ 2 CRS at doses below 13.5 mg) [54].
In the first-line setting, the drug mosunetuzumab is being assessed as monotherapy or in combination with chemotherapy. In phase I/II study GO40554 (NCT03677154), mosunetuzumab monotherapy is being evaluated in patients 80 years of age or older or in patients with untreated DLBCL aged 60–79 years who are ineligible for R-CHOP chemotherapy. Of the 19 evaluable patients, eight patients received the weekly step-up dose of 1/2/13.5 mg while 11 patients received the 1/2/30 mg dose. Treatment was continued for up to a maximum of 17 cycles. The median age was 84 (range: 67–100) years. The ORR was 58% and the CR rate was 42% [55]. Similar efficacy data were shown by the phase Ib/II GO40515 trial (NCT03677141), in which mosunetuzumab was also evaluated in early-stage DLBCL, CHOP chemotherapy eligible. Mosunetuzumab was administered in a weekly step-up dosing regimen at a 1/2/13.5 or 1/2/30 mg dose level in R/R NHL. In the seven patients with R/R NHL, the ORR was 86% with a CR rate of 71% [56]. In the 27 evaluable DLBCL patients, the ORR was 96% and the CR rate was 85% [56]. Grade ≥ 3 AEs occurred in 37 pts (86%). Nineteen patients (53%) with previously untreated DLBCL had mild CRS events. No ICANS events were observed [56].

4. Odronextamab

Odronextamab (REGN1979) is a fully human IgG4-based CD20/CD3 bsAb, hinge-stabilized, which has been evaluated in the NHLs R/R setting. In a phase I study (NCT02290951), odronextamab was administered in a step-up dosing regimen over three weeks followed by a fixed weekly dose until week 12. After this, maintenance dosing was given. Preliminary data is available for 127 patients with R/R NHLs with doses ranging from 0.03 to 320 mg [46]. This cohort included a heavily pre-treated group of patients with DLBCL, grade 1–3a FL and MCL, with 29 patients having received prior CAR T-cell therapy. In patients with R/R grade 1–3a FL, odronextamab, at a dose of ≥5 mg, achieved an ORR of 92.9% and a CR rate of 75.0% [46]. The median DOR was 7.7 months [46]. In patients with DLBCL, excluding those who had received prior CAR T-cell therapy, in those treated at doses ≥ 80 mg (n = 10) the ORR and CR rate were both 60% [46]. The median observed DOR in the DLBCL group was 10.3 months [46]. In those DLBCL patients who relapsed after CAR T-cell therapy, 21 patients were treated at doses ≥ 80 mg, with an ORR of 33.3% and a CR rate of 23.8% [46]. Grade > 3 CRS occurred in 9 pts (7.1%) during the first 2 weeks of step-up dosing and resolved within a median of 2 days (range 1–41) with supportive care measures. No patient discontinued odronextamab treatment due to CRS. Grade 3 neurologic AEs were noted in 3 (2.3%) of patients. None of these events required treatment discontinuation. No grade 4 or higher neurologic AEs were reported [46].

5. Epcoritamab

Epcoritamab is a IgG1 bsAb which binds CD20 and CD3 and is administered via subcutaneous injections. In a phase I/II study (NCT03625037), patients with R/R NHLs received a subcutaneous injection of Epcoritamab at a fixed weekly dose for two 28-day cycles, fortnightly for four cycles, and every four weeks thereafter. Preliminary data presented results for 67 patients (67% with DLBCL, 18% with FL, and 6% with MCL) with an ORR of 66.7% (CR rate of 33.3%) for doses > 12 mg. Notably, of 9% who had received previous CAR T-cell therapy, all responded (two patients achieving a CR and the other two a partial response). Of the seven patients with DLBCL who received a dose ≥ 48 mg, the ORR was 100% (28.6% CRs). High efficacy was also shown in FL patients who received a dose ≥ 0.76 mg with an ORR of 100% (two patients achieved a CR). In the four patients with MCL, responses were observed in two patients with blastoid variant MCL. Data on the duration of response are not yet available. CRS events were all grade 1/2 (58%) with no grade 3/4 events, and limited neurotoxicity was observed (6%, all transient, with 3% at grade 1 and 3% at grade 3). There were no dose-limiting toxicities[9].

6. Novel Perspective and bsAbs in Clinical Development

Although bsAbs hold great promise, it is still challenging to produce bsAbs with high clinical performance and reduced side effects; in addition, the research for new immunological targets and pathways is very active.
For instance, ROR1, a a receptor tyrosine kinase uniformly expressed on the cell surface of malignant B cells, carcinoma, sarcoma, and melanoma solid tumors, is a highly attractive candidate for targeted cancer therapy [57]. NVG-111 is a humanized, tandem scFv bsAb binding ROR1 and CD3 and previously shown to be a potent tumor cell killer in vitro. In vivo it has also been shown to engage a ROR1 membrane-proximal epitope in the Wnt5a-binding Frizzled domain and redirect T-cell activity [58]. An ongoing phase 1/2 study in patients with R/R chronic lymphocytic leukemia (CLL) and MCL is evaluating an escalated doses schedule (of 0.3 to 360 µg/day) via continuous infusion over 3 cycles (each 21 days on, 7 days off). Patients are ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax (clinical trial information: 2020-000820-20). Results are pending [58].
CD22 is an attractive target for B-cell malignancies due to its strong expression on B-lymphoid cell surface. Several CD22-targeting monoclonal Abs, Ab-drug conjugates, radioimmunoconjugates, CAR T-cells, and bsAbs are under investigations. NCT04540796 is an ongoing phase I trial with JNJ-75348780, a bsAb targeting CD3 and CD22 in patients with R/R NHLs, including CLL. Preliminary results have not been published at this time [59].
Immune checkpoint inhibitors have shown high clinical activity in many tumor types; however, only a fraction of patients benefit [60]. In a preclinical setting, combining CD137 agonists with these inhibitors increased antitumor activity, but attempts to translate these observations into the clinic were hampered by systemic toxicity [61]. A bispecific human CD137x programmed death ligand 1 (PD-L1) Ab, MCLA-145, potently activated T-cells and enhanced T-cell priming, differentiation, and memory recall responses. In vivo, the antitumor activity of MCLA-145 was superior to immune checkpoint inhibitor comparators and was related to intra-tumor recruitment and expansion of CD8+ T-cells. No graft-versus-host disease was detected, unlike other Abs that inhibit the programmed death (PD)-1 and PD-L1 pathways. MCLA-145 is currently being evaluated in an open label, single-agent dose-escalation study with expansion cohorts for confirmation of dose/safety and preliminary efficacy in advanced or metastatic malignancies (NCT03922204).

This entry is adapted from the peer-reviewed paper 10.3390/antib11010016

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