2020 ASH Highlights: Bispecific Antibody Therapies from Regeneron, Roche, Johnson & Johnson, and Pfizer Take Center Stage

The 62nd Annual Meeting of the American Society of Hematology (ASH) will be held from December 5 to 8, 2020. Bispecific antibodies, as a form of immunotherapy for hematologic malignancies, have also become one of the focal points of this year’s conference. Bispecific antibody therapy represents another approach to leveraging the patient’s immune system, specifically T cells, to kill tumors. One end of these antibodies binds to antigens on the surface of cancer cells, while the other end binds to T-cell receptors on the surface of T cells, thereby recruiting T cells to the vicinity of cancer cells and activating their cytotoxic activity against the tumor cells.

According to the abstracts from the ASH Annual Meeting, multiple bispecific antibodies from companies such as Regeneron, Roche, Janssen (a subsidiary of Johnson & Johnson), and Pfizer will be prominently featured at this year’s conference. In this article, we highlight several highly anticipated investigational bispecific antibody therapies, examining the new research progress they have achieved in the treatment of relapsed/refractory hematologic cancers.

1、Odronextamab（REGN1979）

Company: Regeneron

Target: CD20 x CD3

Indications: Refractory B-cell non-Hodgkin lymphoma

Odronextamab is a CD20 x CD3 bispecific antibody generated by Regeneron through its proprietary Veloci-Bi bispecific antibody platform. This technology platform enables the generation of full-length bispecific antibodies similar to natural antibodies, which can be manufactured using standard antibody production technologies and exhibit pharmacokinetic properties comparable to those of conventional antibodies. REGN1979 is designed to kill cancer cells by binding to the B-cell tumor protein (CD20) and the T-cell receptor of the immune system (CD3).

At this year’s annual meeting, researchers will present updated data on odronextamab for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL). Updated results from ongoing dose-escalation and early dose-expansion studies demonstrate that odronextamab exhibits robust single-agent antitumor activity in patients with highly refractory B-NHL. Durable complete response (CR) rates were observed in patients with both indolent and aggressive B-NHL, including those refractory to CAR-T cell therapy. Furthermore, odronextamab demonstrated an acceptable safety and tolerability profile. Currently, a global Phase 2 clinical trial is underway to further evaluate the efficacy of odronextamab in treating relapsed/refractory B-NHL.

It is worth noting that in April 2020, Zai Lab entered into a regional strategic collaboration with Regeneron, securing the rights to develop and exclusively commercialize odronextamab for oncology-related indications in Greater China (mainland China, Hong Kong, Macau, and Taiwan). In September this year, odronextamab was approved in China to initiate clinical trials in patients with B-cell non-Hodgkin lymphoma (B-NHL).

2、Mosunetuzumab

Company: Roche

Target: CD20 x CD3

Indication: Diffuse Large B-Cell Lymphoma

Although the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) demonstrates significant efficacy as a first-line treatment for diffuse large B-cell lymphoma (DLBCL), 35%–40% of patients receiving R-CHOP ultimately die from the disease. Therefore, there is an urgent clinical need for improved therapeutic approaches. Mosunetuzumab is a bispecific antibody developed by Genentech, a member of the Roche Group, that binds to T cells. By engaging CD3 on T cells and CD20 on B cells, it directs T cells to eliminate malignant B cells.

At this conference, researchers reported study data (GO40515 study) on mosunetuzumab plus CHOP (M-CHOP regimen) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) and newly diagnosed diffuse large B-cell lymphoma (DLBCL). As of June 3, 2020, a total of 43 patients had received M-CHOP treatment.

The study results showed that among patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL) treated with M-CHOP (n=7), the overall response rate (ORR) was 86%, with 71% of patients achieving complete response (CR). Among 36 patients with diffuse large B-cell lymphoma (DLBCL), 27 had initiated treatment at least 3 months prior to the data cutoff date; in these patients, the ORR was 96% and the CR rate was 85%. The study concluded that preliminary data indicate mosunetuzumab in combination with CHOP demonstrates high response rates and manageable safety in patients with R/R NHL and previously untreated DLBCL.

3、IGM-2323

Company: IGM Biosciences

Target: CD20 x CD3

Indications: Advanced B-cell Malignancies

IGM-2323 is a novel bispecific antibody developed by IGM Biosciences, based on a pentameric IgM structure and featuring a recombinant J chain fused to an anti-CD3 scFv. Its structure comprises ten high-affinity CD20-binding domains and one high-affinity CD3-binding domain. In preclinical studies, IGM-2323 has been demonstrated to bind irreversibly to CD20-expressing cells and deplete them in human peripheral blood mononuclear cell (PBMC) cultures with limited cytokine secretion.

At this conference, researchers will present data from the first-in-human, dose-escalation Phase 1 trial evaluating the safety, tolerability, biomarkers, and preliminary antitumor activity of IGM-2323 in adults with B-cell malignancies. As of June 12, 2020, eight patients had been treated across four dose levels. Preliminary results indicated improved safety and tolerability of IGM-2323 at higher doses, and suggested that IGM-2323 may have a novel mechanism of action compared to other T-cell-engaging antibodies.

4、Teclistamab（JNJ-64007957）

Company: Janssen

Target: BCMA x CD3

Indications: Relapsed/Refractory Multiple Myeloma

Teclistamab is a bispecific antibody targeting B-cell maturation antigen (BCMA) and TBispecific antibody targeting CD3 receptors expressed on cells, which can recruit T cells to the vicinity of tumor cells and activate them to attack the tumor cells. Preclinical studies have shown that teclistamab can kill cell lines and myeloma cells derived from patients with multiple myeloma (MM).

Researchers will present the latest results from the Phase 1 study of teclistamab in multiple myeloma at this year’s ASH meeting. As of July 20, 2020, 84 patients had received intravenous teclistamab, and 44 patients had received subcutaneous teclistamab.

Study data showed that the overall response rate (ORR) in patients was 63.8%, with 51% of patients achieving a very good partial response (VGPR) and nine patients achieving complete response (CR). The study identified 1,500 µg/kg as the recommended Phase 2 dose (RP2D) for the subcutaneous injection group. Among the 48 responding patients across both the intravenous and subcutaneous cohorts, the median time to first response was 1 month, and the median duration of response had not been reached; notably, 38 of these responders maintained their response during treatment periods ranging from 1.6 to 21.3+ months. Among evaluable patients with CR for minimal residual disease (MRD), 80% (4/5) in the intravenous cohort and two patients in the subcutaneous cohort achieved MRD negativity.

The study suggests that teclistamab has a manageable safety profile in both the intravenous and subcutaneous injection groups, including low-grade cytokine release syndrome (CRS), low severe infection rates, and neurotoxicity rates. Durable responses were observed in both groups. These findings will support Phase 2 monotherapy trials and future combination studies.

5、REGN5458

Company: Regeneron

Target: BCMA x CD3

Indication: Relapsed/Refractory Multiple Myeloma

REGN5458 is a bispecific antibody targeting BCMA and CD3, developed by Regeneron based on its VelocImmune and VelociBi technology platforms. VelocImmune is a next-generation transgenic mouse platform featuring a humanized B-cell immune system, capable of generating optimized fully human antibodies. The VelociBi platform produces full-length bispecific antibodies similar to natural antibodies, exhibiting pharmacokinetic properties comparable to those of fully human antibodies. REGN5458 binds to both BCMA and CD3, thereby targeting MM cells via BCMA while engaging T-cell effector functions.

At this conference, researchers will present updated Phase 1 trial data on REGN5458 monotherapy in patients with relapsed/refractory multiple myeloma (MM). Enrolled patients had previously received ≥3 prior lines of therapy, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. As of June 15, 2020, 45 patients had been treated with REGN5458.

Study data showed that the overall response rate (ORR) across all dose levels was 35.6% (60% at the highest dose level), with 81.3% of responders achieving at least a very good partial response; 31.3% of patients achieved complete response; the duration of response (DoR) exceeded 4 months in 43.8% of responders and exceeded 8 months in 18.8%; the ORR in patients with extramedullary plasmacytomas was 16.7%. The study indicated that updated data demonstrate REGN5458 has an acceptable safety profile and durable efficacy in patients with relapsed/refractory multiple myeloma (MM).

6、PF-06863135

Company: Pfizer

Target: BCMA x CD3

Indication: Relapsed/Refractory Multiple Myeloma

PF-06863135 is a bispecific antibody developed by Pfizer that simultaneously targets BCMA and CD3. At this conference, researchers will present the latest study data on PF-06863135 for the treatment of patients with relapsed/refractory multiple myeloma (MM). As of April 15, 2020, 18 patients received subcutaneous injections of PF-06863135 (at doses of 80 μg/kg, 130 μg/kg, 215 μg/kg, and 360 μg/kg). All these patients had previously been treated with anti-CD38 monoclonal antibodies, and four of them had also received BCMA-targeted antibody-drug conjugates or CAR-T therapy. As of the data cutoff date, dose escalation was ongoing, and the maximum tolerated dose (MTD) had not been reached.

Trial data showed that the objective response rate was 33% across all subcutaneous injection dose groups, and 75% in the two high-dose groups (215 μg/kg and 360 μg/kg). Two patients achieved a very good response. Seven patients had stable disease as their best response. Exposure to PF-06863135 increased proportionally with dose. Compared with intravenous administration, subcutaneous administration resulted in a lower maximum concentration (Cmax) and a longer absorption phase, with a median time to Cmax of 3–7 days.

The study suggests that adverse events associated with subcutaneous administration of PF-06863135 are generally manageable, with most patients reporting grade 1–2 cytokine release syndrome (CRS). Six out of eight patients who received the two highest dose levels of subcutaneous PF-06863135 demonstrated a response. Compared to intravenous administration, subcutaneous injection modulates Cmax, thereby enabling the administration of higher doses without an observed increase in CRS severity.

7、TNB-383B

Company: Teneobio/AbbVie

Target: BCMA x CD3

Indications: Relapsed/Refractory Multiple Myeloma

TNB-383B is a bispecific antibody developed by Teneobio that simultaneously targets BCMA and CD3, designed to direct the body’s immune system to target and kill tumor cells expressing the BCMA antigen. In February 2019, AbbVie entered into a collaboration with Teneobio and its subsidiary TeneoOne to jointly develop and commercialize TNB-383B.

At this conference, researchers presented the first-in-human clinical trial data for TNB-383B. This Phase 1 dose-escalation and dose-expansion study enrolled patients with relapsed/refractory multiple myeloma who had received at least three prior lines of therapy, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. The primary objectives of the study were to assess the safety/tolerability and clinical pharmacology of TNB-383B, and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D).

As of July 13, 2020, 38 subjects had received TNB-383B (0.025–40 mg). Study data showed that the maximum tolerated dose (MTD) of TNB-383B was 40 mg, without the need for stepwise or split dosing. A preliminary objective response rate (ORR) of 52% (12/23) was observed at doses ≥5.4 mg, with favorable and durable responses (lasting up to 24 weeks) despite once-every-three-weeks dosing.

Other

In addition to the aforementioned drugs, data on several bispecific antibodies were also presented at this conference, including Roche’s FcRH5 x CD3 bispecific antibody, Johnson & Johnson’s GPRC5D x CD3 bispecific antibody, and Affimed’s CD30 x CD16A bispecific antibody. Due to space limitations, these will not be discussed individually in this article. We look forward to the smooth progress of subsequent research on these bispecific antibodies, bringing new treatment options to patients with relapsed/refractory hematologic cancers as soon as possible.

References:

[1] Abstracts from the 62nd Annual Meeting of the American Society of Hematology (ASH). Retrieved Nov 09, 2020, From https://ash.confex.com/ash/2020/webprogram/start.html

[2] Official websites and public information of various companies

Source: Medical Outlook

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