First-in-human results at fall conferences reveal rapid expansion in the target space for bispecifics
The target space for bispecific antibodies is rapidly expanding, and early clinical data are on display at ASH and SITC.
By Lauren Martz, Senior Editor
December 5, 2020 3:11 AM UTC
Bispecific antibodies are starting to diverge from CAR Ts as they venture into new targets and indications in the clinic.
First-generation T cell-engaging bispecific antibodies have mirrored the trajectory of CAR T cell therapies for years, using the same CD19, CD20 and BCMA targets to draw T cells to destroy B cell malignancies.
With a simpler format for manufacturing and delivery than the cell therapies, interest in bispecifics has been ticking up at major medical conferences each year — and this year represents a turning point.
Interest is exploding, and companies are generating clinical data in new target spaces that CAR Ts haven’t yet touched. They’re also exploring next-generation bispecific constructs with new functionalities beyond engaging T cells as they transition the modality into solid tumors.
BioCentury’s analysis of the abstracts released ahead of the American Society of Hematology (ASH) virtual meeting that kicks off on Dec. 5 and the Society for Immunotherapy of Cancer (SITC) virtual meeting held last month finds that bispecific antibodies represent 21% of the new therapies sharing clinical data for the first time, the majority of which involve new targets for the modality.
The new targets in the first-in-human dataset reflect the interest in using bispecifics in new ways.
While several are T cell engagers that bind CD3 on the immune cells plus a target on the tumor cell surface, nearlyas many abstracts feature a format designed to hit two different checkpoint targets, either on T cells or cancer cells, to help overcome resistance to individual checkpoint inhibitors.
A third bispecific construct that uses a T cell receptor (TCR) structure to bind a tumor target rather than an antibody domain makes appearances in the meetings’ preclinical abstracts and presentations and expands the target space for solid tumors; the structure has produced clinical data outside the meetings.
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“I think with bispecifics, we’re just at the tip of the iceberg,” said Andres Sirulnik, SVP of translational & clinical sciences, hematology at Regeneron Pharmaceuticals Inc. (NASDAQ:REGN). “One aspect of this technology is harnessing the power of the immune system to kill tumors, and there’s no question that’s an extremely powerful application, but we’re now looking at different ways to approach bispecific antibodies.”
Bispecifics have been a hot topic at ASH for years, with the number of abstracts covering the modality growing each year in201 6-19, but they’ve always been dwarfed by standard antibodies and small molecules at the meeting.
This year’s first-in-human dataset paints a different picture, with bispecific abstracts outnumbering small molecule abstracts, and new modalities — including bispecifics, CAR Ts and other cell therapies — representing nearly five-times as many first-in-human data readouts as small molecules. mAbs were absent from first-in-human abstracts at ASH, though there were plenty at SITC.
Bispecifics ranked second among first-in-human readouts at SITC. And while the novel bispecifics reported at ASH are all T cell engagers, the SITC meeting featured data on dual checkpoint-engaging bispecifics in solid tumors, where T cell engaging bispecifics have made less headway.
Validated targets such as CD19, CD20 and BCMA are represented in the ASH abstracts, but half of the bispecific targets featured have yet to be tested in late-stage trials of bispecifics or CAR T cells.
And none of the bispecific targets at SITC have progressed beyond early clinical trials for bispecific or CAR Ts.
A dive into preclinical data shared at both meetings suggest the first-in-human data is only the beginning of a new wave of bispecific innovation that’s expanding the target space. Companies and academic teams are also exploring TCR-based bispecifics, bispecific prodrugs selectively activated in the tumor microenvironment, and costimulatory bispecifics designed to increase activation of the T cells they draw to cancers.
“As more targets are coming to life, I think the use of bispecifics will allow us to better home in on the tumors, but we won’t always be engaging T cells to do that. We can explore different mechanisms. I think mechanisms like ADC bispecifics will be coming to life. That’s something I’m sure you’ll be hearing about soon,” Sirulnik told BioCentury.
ASH and SITC data indicate that T cell engagers are moving beyond the initial target pool they shared with CAR T cells.
Both modalities rely on targets expressed on the cancer cell surface to draw antitumor T cells to cancers, and both require those tumor targets to be either highly selective for cancer cells or co-expressed only on healthy tissues that patients can temporarily live without. That led both modalities first to B cell malignancies, where knocking out healthy B cells expressing targets such as CD19, CD20 and BCMA is an acceptable on-target toxicity.
Now, T cell engagers against targets that CAR Ts haven’t touched are moving through the clinic.
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One reason companies are turning to bispecifics to explore new targets is that the modality might be better suited for new target validation.
Although bispecifics have generally come in with lower efficacy than CAR T cells, they have a much simpler manufacturing process, administration procedure and cost structure. They’ve also shared some of the same safety issues as CAR Ts and have been limited by short half-lives, but adjusted dosing schedules and next-generation compounds have addressed those issues.
At ASH, B cell malignancies still dominate among T cell engager candidates reading out for the first time, but at least one company — Janssen — is exploring a new target within that space.
Janssen is reporting initial data on multiple myeloma (MM) T cell engager talquetamab against the novel target GPRC5D (No. 290). Craig Tendler, VP of oncology clinical development & global medical affairs at Janssen, told BioCentury that like BCMA, the target is highly expressed on MM cells, with limited expression on other tissues. It also doesn’t seem to be shed from the cancer cells.
“Based on the profile, we think this could play an important role either after BCMA targeted therapy, or maybe ahead or in combination with BCMA targeted therapy to delay or prevent the emergence of resistance,” he said.
The only first-in-human bispecific ASH abstract targeting an indication outside of B cell malignancies comes from Aptevo Therapeutics Inc. (NASDAQ:APVO) (No. 2858). The company will share initial safety data for its CD123 x CD3 antibody for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). CD123 is expressed at much higher levels on AML cells than healthy stem and progenitor cells, but there’s still a risk of depleting the healthy cells.
New targets for T cell engagers also appear outside the first-in-human abstracts at ASH. For example, Genentech Inc. will share a pair of abstracts on BFCR4350A, a CD3 x FcRH5 antibody in Phase I for MM (No. 282; 3213).
Hemogenyx Pharmaceuticals LLC will share preclinical data for a FLT3 x CD3 bispecific for AML (No. 2269).
Evidence bispecifics are making progress in the transition from hematological malignancies to solid tumors was also on display. T cell engagers weren’t represented in the first-in-human data at SITC, but they did account for half of all other abstracts mentioning bispecifics at the conference, most of which covered preclinical compounds for solid tumors.
Companies are approaching solid tumors with T cell engaging bispecifics in three ways: they’re finding highly selective cell surface targets on tumors, using TCR structures rather than antibody chains as the tumor binding domain, and creating ways to restrict activity to the tumor microenvironment.
Amgen Inc. (NASDAQ:AMGN) shared several abstracts on bispecific constructs that stick to the standard format for solid tumors. It presented on bispecifics targeting PSMA (No. 340) and STEAP1 (No. 718) for prostate cancer, and targeting DLL3 for small cell lung cancer (No. 359).
Several companies are taking the TCR route, which expands the tumor targets that can be addressed beyond surface proteins by binding fragments of intracellular proteins when presented by HLA on the tumor cell surface.
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Roche (SIX:ROG; OTXQX:RHHBY) shared preclinical data on TCR bispecifics targeting CEA and WT1 (No. 653), and Complete Omics Inc. shared preclinical data on TCR bispecifics targeting a set of common p53 neoantigens (No. 629).
Amunix Pharmaceuticals Inc. is expanding the target space for solid tumors by creating bispecific prodrugs. The company shared preclinical data on a HER2 x CD3 bispecific that’s activated by proteases in the tumor microenvironment. T cell engagers targeting HER2 would be toxic to normal tissues if active outside the tumor microenvironment (No. 613).
Another construct that’s just emerging is costimulatory bispecifics. These are T cell engagers, but they engage a different target on the T cells.
“CD3 engagers attract T cells to the tumor and provide an ignition key to their tumor killing ability, but we know that T cells require a second signal: a pedal on the gas,” said Andres Sirulnik, SVP of translational & clinical sciences, hematology at Regeneron Pharmaceuticals Inc. (NASDAQ:REGN).
Regeneron is developing costimulatory T cell engagers that target CD28 on T cells, though the company hasn’t disclosed the tumor antigens it will pursue.
At SITC, Xencor Inc. (NASDAQ:XNCR) shared a preclinical abstract covering B7H3 x CD28 and PD-L1 x B7H3 costimulatory bispecifics, showing that they synergize with standard T cell engagers targeting CD3 in preclinical models (No. 697).
Two bispecific abstracts at SITC also covered NK cell engaging antibodies, which target CD16a on NK cells and a tumor antigen. Affimed N.V. (NASDAQ:AFMD) shared data on its CD30 x CD16a NK cell engager AFM13 at the meeting (No. 531), and an academic group from the Netherlands reported preclinical data for a CD16a x EGFR bispecific (No. 634).
An alternative bispecific structure at SITC
The first-in-human dataset from SITC is made up of the bispecific subtype that binds two different checkpoints for a more targeted effect that’s designed to reduce resistance.
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One example is the CTLA-4 x OX40 bispecific ATOR-1015 from Alligator Bioscience AB (SSE:ATORX)(No. 369). The compound was designed to decrease the toxicity of anti-CTLA-4 mAbs by better restricting the therapy to the tumor microenvironment. The idea is that by requiring the therapy to bind and modulate two checkpoint targets that are both overexpressed by T cells in the microenvironment, the activity will be better directed to the tumor.
FS118, a bispecific antibody from F-Star Therapeutics Ltd., hits one checkpoint on T cells and another on the tumor, but it’s goal isn’t to bring the T cell to the tumor. Instead, it’s designed to overcome resistance to checkpoint inhibitor therapy. The antibody targets PD-L1 and LAG3, which is often upregulated in tumors refractory to PD-1 and PD-L1 inhibitors (No. 395).
Genmab A/S (NASDAQ:GMAB; CSE:GMAB) is also presenting early clinical data for its PD-L1 x 4-1BB bispecific GEN1046 in solid tumors (No. 412) at SITC.
Other trends in the earliest clinical readouts
The first-in-human datasets from ASH and SITC also cover other types of emerging immune cell therapies.
At ASH, Orca Bio will share first-in-human data on an engineered Treg cell therapy that’s designed to prevent graft-versus-host reactions during stem cell transplant (No. 354).
In8bio Inc. will share early clinical data on its γδ T cell therapy, a subset of T cells that has attracted major venture dollars and deals over the past five years (No. 3260).
The γδ trend was also present at SITC. ImCheck Therapeutics S.A.S. presented initial data on ICT01, an antibody that targets BTN3A to activate γδ T cells (No. 316).
Therapies that reprogram myeloid cells have been attracting attention at scientific conferences in recent years, and first-in-human data for at least one was shared at SITC. GB1275, an CD11b modulator from Gossamer Bio Inc. (NASDAQ:GOSS), works by converting immunosuppressive macrophages to an immunostimulatory phenotype (No. 388).
Immune stimulator-antibody conjugates are also starting to emerge as a new class of therapies. The concept is a newer take on antibody-drug conjugates and involves linking a tumor-binding antibody that will trigger macrophages to engulf tumor cells to a toll-like receptor that will shift the tumor environment from cold to hot to enhance the effect.
Novartis AG (NYSE:NVS; SIX:NOVN) shared first-in-human data at SITC on NJH395, an anti-HER2 antibody conjugated to TLR7/8 (No. 378). At least three other abstracts presented at SITC cover preclinical data on immune stimulator-antibody conjugates.
Bispecific antibodies are starting to diverge from CAR Ts as they venture into new targets and indications in the clinic.
First-generation T cell-engaging bispecific antibodies have mirrored the trajectory of CAR T cell therapies for years, using the same CD19, CD20 and BCMA targets to draw T cells to destroy B cell malignancies...
