Strength target B7-H3: Immunity rookies gradually reveal their edge

Recently, Tianjing Biotechnology announced that the Phase II clinical trial application for the combination of ebrolizumab and Keytruda (pembrolizumab) for the treatment of solid tumors has been accepted by the NMPA, marking that the first domestic B7-H3 (also known as CD276) drug will be accepted.

Members of the B7 family are popular targets for immunotherapy.

B7-H3: Immune rookies worthy of attention

In the course of immune response, natural T cells bind to their T cell receptors (TCR), interact with the complex of MHC and peptide expressed by antigen presenting cells, and become the first level signal of T cell activation

B7 family proteins have been shown to be involved in regulating T cell responses

The immune checkpoint molecules of the B7 family and their receptors, costimulatory and co-inhibitory receptors are marked with (+) and (-) respectively (Reference [3])

Different B7 molecules produce different co-stimulatory signals when regulating immune cell response, as shown in the figure above, B7-H1/PD-1, CD80/CTLA4, CD86/CTLA4.

B7-H3 (CD276) is a type I transmembrane protein, which belongs to the B7 immune co-stimulatory and co-suppressive family.

B7-H3 protein structure (Reference [5])

In the early stage of the discovery of B7-H3, it was mainly proved to be a costimulatory receptor, promoting the proliferation of CD4+ and CD8+ T cells, inducing cytotoxic T cells, and selectively stimulating interferon in the case of T cell receptor signaling γ (IFN-γ) to produce immunostimulatory function [4,6]

In terms of molecular mechanism, although the intracellular domain of B7-H3 protein is very short, no known signal motif has been found; however, B7-H3 protein indirectly activates NF-kB, PI3K/Akt and JAK/STAT3 pathways to induce cells Survive and proliferate

Schematic diagram of B7-H3 signal (Reference [10])

Therefore, targeting B7-H3 can reduce cell proliferation, progression and metastasis, and is expected to provide new treatment options and better clinical results

B7-H3: The clinical strength is prominent, and the edge is gradually revealed

Currently, new technologies for drug development are emerging one after another

Schematic diagram of drug forms targeting B7-H3 (Reference [12])

According to NextPharma's data, there are 14 B7-H3 drugs in clinical development around the world

Ebutuximab is the first monoclonal antibody that targets the B7-H3 protein and has an Fc-optimized function

Preclinical data of ebrolizumab (MGA271) (Reference [13])

In clinical studies, according to the data published at the 2018 Annual Meeting of the Society for Cancer Immunotherapy (SITC), the objective response rate (ORR) of ebrolizumab combined with PD-1 monoclonal antibody in the treatment of SCCHN patients reached 33.

Treatment data of ebrolizumab (source: MacroGenics)

At the same time, in the first-line treatment of SCCHN/NSCLC, including NSCLC with low PD-L1 expression (<1%), the combination therapy of ebrolizumab and immunotherapy also performed well

Treatment data of ebrolizumab (source: MacroGenics)

In general, the combination of ebrolizumab and pembrolizumab not only showed good tolerability, the clinical data also showed the potential to be better than the historical data of immunotherapy, and the ORR was significantly improved

Treatment data of ebrolizumab (source: MacroGenics)

Of course, this is only the preliminary clinical data of ebrotuzumab

MacroGenics has also developed an antibody-conjugated drug MGC018 for B7-H3, and disclosed relevant clinical results at this year's ESMO conference
.
The data showed that of 32 (mCRPC, n=16; NSCLC, n=16) tumor patients who received MGC018 treatment and had an evaluable efficacy, 8 patients (25%) had lesions reduced by more than 30% compared with baseline, achieving partial remission.
Including 4 cases of mCRPC (2 confirmed PR, 2 unconfirmed PR) patients and 4 NSCLC patients (unconfirmed)
.

MGC018 treatment data (Source: MacroGenics)

In addition, the B7-H3 antibody conjugate drug DS-7300 developed by Daiichi Sankyo is also worthy of attention
.
At this year's ESMO meeting, DS-7300 also announced early clinical data, which initially showed its anti-tumor effect during the dose expansion
.
In the full-dose group, 24.
1% (15/70) of the patients showed an objective response (PR)
.

DS-7300 treatment data (Source: ESMO)

In addition, the radioimmunotherapy 131I-omburtamab, which Saisheng has domestic rights and interests, has applied for listing, but clinical research has not been carried out in China
.
However, in terms of the current clinical data of several representative drugs, Ebutuximab has potential safety advantages over ADC drugs, including the overall incidence of adverse events and serious adverse events (≥ grade 3) And treatment interruption caused by adverse events
.

Safety data of ebrolizumab (source: MacroGenics)

MGC018 safety data (Source: MacroGenics/ESMO2021)

DS-7300 safety data (source: ESMO2021)

Of course, the clinical effectiveness and safety of Ebutuximab and its other two drugs are not yet fully mature, and the final therapeutic potential of the drugs needs further clinical research
.
However, current data have shown the clinical benefits of drugs such as ebrotuzumab, including confirmed clinical partial remission and disease control
.

Considering that B7-H3 is widely expressed in many tumor types, it means that drugs targeting B7-H3 have a broad therapeutic field in theory, and it is believed that its clinical and commercial value will be continuously tapped and gradually released
.

Concluding remarks

In the upsurge of tumor immunotherapeutic drug development, successful targets related to signal transduction of B7 family members such as CTLA4 and PD-1 have emerged.
The industry is also striving to find new next-generation immune targets with the same therapeutic and commercial potential.

.
B7-H3, as a B7 family member protein widely expressed in many tumor species, has gradually entered the field of vision of developers
.

The radioimmunotherapy targeting B7-H3, 131I-omburtamab, has been developed for the treatment of neuroblastoma and has been applied for marketing, providing support for the druggability of B7-H3
.
In addition, there are many other B7-H3 targeted drugs in different forms that are being explored in more solid tumors.
Although more of them are in the early stage, they have also shown signs of clinical benefit
.
At present, the fierce competition among companies on B7-H3 has not yet appeared, but B7-H3 has also begun to show its edge, and we look forward to more breakthrough clinical data in the future to meet the clinical needs of patients with B7-H3 positive or overexpression
.

Reference

[1] Elodie Picarda, et al.
Molecular Pathways: Targeting B7-H3 (CD276) forHuman Cancer Immunotherapy.
Clin Cancer Res; 22(14): 3425-3431

[2] Zang X, Allison JP.
The B7 Family and Cancer Therapy: Costimulation and Coinhibition.
Clin Cancer Res (2007) 13:5271–9

[3] Shuo Yang, et al.
B7-H3, a checkpoint molecule, as a target forcancer immunotherapy.
Int.
J.
Biol.
Sci.
2020; 16(11): 1767-1773

[4]Andrei I, etal.
B7-H3: A costimulatory molecule for T cell activation and IFN-γ production.
natureimmunology, 2001, 2(3): 269-274

[5]Filippos Kontos, et al.
B7-H3: an attractive target for antibody-based immunotherapy.
Clin Cancer Res.
2021 March 01; 27(5): 1227–1235

[6] X Sun, et al.
Mouse B7-H3 induces antitum or immunity.
Gene Therapy (2003), 10, 1728–1734

[7]Theodoros Michelakos, et al.
B7-H3 targeted antibody-based immunotherapy of malignant diseases.
Expert Opinion on Biological Therapy, https://doi.
org/10.
1080/14712598.
2021.
1862791

[8] Jose R Castellanos, et al.
B7-H3 role in the immune landscape of cancer.
Am J Clin Exp Immunol 2017;6(4):66-75

[9] Gao Chuntao, et al.
Research progress of B7-H3 in tumor immunity.
International Biomedical Engineering, 2020, 43(4): 324-328

[10] Yi Li, et al.
B7-H3 promotes the proliferation, migration and invasiveness of cervical cancer cells and is an indicator of poor prognosis.
ONCOLOGYREPORTS, 2017, 38: 1043-1050

[11] Karine F Karlsen.
B7-H3 in Cancer Beyond Immune Regulation.
Trendsin Cancer, 2018: 401-404

[12] Wu-Tong Zhou, et al.
B7-H3/CD276: An Emerging Cancer Immunotherapy.
Front Immunol, 12: 701006

[13] Deryk Loo, et al.
Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with PotentAntitumor Activity.
Clin Cancer Res,18(14): 3834-3845