B7-H3 Target Beacon Fire Resurrection

On April 15, Bio-Tech announced the clinical approval of BAT8009, an ADC drug targeting B7-H3
.
On March 9, Bio-Tech announced that another ADC drug under the drug, BAT8006, was approved for clinical use.
BAT8006 is an ADC drug targeting FRα
.
The re-launch of FRα and B7-H3 ADC drugs marks that Bio-Thera will fight again on the ADC track
.
Of course, the emerging targets of B7-H3 and FRα also mean that the available data are relatively limited, and risks and benefits coexist
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01 Introduction to B7-H3 target T cell activation depends on two signals, including the first signal and the second signal
.
The first signal refers to the specific recognition of the antigen peptide-MHC molecule complex on the antigen presenting cell (APC) and the T cell receptor TCR, that is, the recognition of the antigen by T cells; the second signal refers to the surface of the T cell and the antigen presenting cell.
There are many paired co-stimulatory molecules that interact with each other to generate co-stimulatory signals, namely costimulation
.
It is generally believed that B7 binds to receptors in cells (mainly T cells) and acts as a second signal
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For example, B7-1 or B7-2 on the surface of antigen presenting cells (APC) binds to CD28 on the surface of T cells to promote the proliferation, secretion and up-regulation of anti-apoptotic genes of T cells; while binding to CTLA-4 inhibits the further development of T cells Activation facilitates the escape of tumor cells
.
Although B7-1 can bind to both CD28 and CTLA-4, the binding affinity to CTLA-4 is more than 20 times that of CD28
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B7 family members are widely expressed in non-lymphoid tissues, and different B7 molecules produce positive and negative co-stimulatory signals when regulating immune cell responses
.
At present, more than 10 kinds of B7 protein molecules have been discovered, of which the most studied include B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1), B7-H2 (ICOSL), etc.

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It is precisely because of the role of part of the B7 protein that the function of T cells is inhibited, resulting in immune escape of tumors
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Therefore, by blocking the binding of B7 to its ligands, it is expected to improve the efficacy of tumor therapy
.
For example, in recent years, PD-(L)1 inhibitors and CTLA-4 inhibitors have been accurately verified in the clinic and have shown good therapeutic effects in various tumors
.
B7-H3, also known as CD276, is an important immune checkpoint molecule of the B7 family
.
B7-H3 is mainly expressed on the surfaces of non-immune cells such as fibroblasts, endothelial cells, and osteoblasts, as well as on the surfaces of activated APCs and NK cells.
Studies have shown that B7-H3 is highly expressed in melanoma, leukemia, breast cancer, prostate cancer, etc.
Overexpression on tumor surface is closely related to tumor growth, metastasis, recurrence and poor prognosis
.
The receptor for human B7-H3 has not been identified, and in mouse models, a trigger receptor TLT-2 expressed in the myeloid cell receptor family has been suggested as a potential receptor for mouse B7-H3
.
Currently, the exact mechanism of B7-H3 remains unclear, but it is thought to be involved in costimulatory and co-inhibitory pathways
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On the one hand, early studies believed that B7-H3 is a co-stimulatory receptor that promotes the proliferation of CD4+ and CD8+ T cells and stimulates the production of interferon gamma (IFN-γ); on the other hand, more and more studies in recent years have shown that B7-H3 is a co-inhibitory receptor, which plays a role in tumor immune escape by inhibiting T cells
.
At present, the development of drugs targeting B7-H3 targets is mainly B7-H3 inhibitors, which can achieve anti-tumor effects through specific blocking of B7-H3
.
02 Current research status of drugs targeting B7-H3 Although the molecular mechanism of B7-H3 is still unclear, as a potential immune checkpoint molecule, its tumor immunotherapy prospects have attracted much attention
.
At present, the development of B7-H3 target involves drugs such as monoclonal antibody, double antibody, ADC, CAR-T and so on.

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(1) Monoclonal antibody MGA271 (enoblituzumab) is a humanized B7-H3 monoclonal antibody developed by MacroGenics, which is currently in clinical phase II
.
MGA271 is developed based on MacroGenics' Fc-optimized platform.
Its antigen-binding fragment has high affinity for B7-H3 and exerts anti-tumor effect through ADCC
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Fc optimization technology can enhance the affinity for the activating CD16A FcγR and reduce the affinity for the inhibitory FcγR CD32B, enhancing effector functions such as ADCC
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In a phase I study (NCT01391143), enoblituzumab was tolerated at doses up to 15 mg/kg and demonstrated a favorable safety profile with no drug-related adverse reactions (TRAEs) leading to study discontinuation
.
The combination of enoblituzumab and PD-1 inhibitors is promising
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At the 2018 SITC, MacroGenics announced clinical data of Enoblituzumab in combination with pembrolizumab
.
The phase I/II clinical trial (NCT02475213) showed that the overall response rate of the combination of enoblituzumab and pembrolizumab nearly doubled compared with the anti-PD-1 blockade alone
.
For squamous cell carcinoma of the head and neck (SCCHN), the combination group achieved an objective response rate of 33.
3%, and for non-small cell lung cancer, the combination group achieved an objective response rate of 35.
7%
.
Regarding safety, 27.
1% of patients (N = 133) experienced grade 3 or higher AEs, 6.
8% of patients withdrew due to AEs, and 1 patient died due to an adverse event of pneumonia
.
Overall, combination therapy has comparable TRAE to PD-1 inhibitor monotherapy
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In addition to the combination with PD-1 mAb, clinical trials of MGA271 in combination with ipilimumab (CTLA-4) and PD-1 and LAG-3 bispecific antibody (tebotelimab) (NCT04634825) are ongoing
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In July 2019, I-Mab signed an agreement with MacroGenics to jointly develop and commercialize enoblituzumab.
I-M Bio will lead the clinical development and sales of enoblituzumab in Greater China and participate in the global clinical research and development led by MacroGenics
.
MacroGenics will receive an upfront payment of $15 million, with the potential to receive up to $135 million in potential development and registration milestone payments
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(2) ADC drug DS-7300 is an ADC drug developed by Daiichi Sankyo that targets B7-H3 and is currently in clinical phase
I.
The DS-7300 is also developed based on the ADC platform patented by Daiichi Sankyo - DXd-ADC
.
DS-7300 consists of three parts, one is an IgG1 monoclonal antibody targeting B7-H3, the other is a tetrapeptide cleavable linker, and the third is a DNA topoisomerase inhibitor DXd, DAR=4
.
At ESMO 2021, Daiichi Sankyo announced the early phase I data of DS-7300.
Among 70 patients with advanced tumor, the objective response rate was 21.
42%, including 10 patients with partial response and 5 patients with pending partial response , and another 32 patients reported stable disease (SD = 45.
71%)
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In terms of safety, no dose-limiting toxicity was observed, and 31.
4% of patients experienced grade 3 or higher TRAEs, the most common being anemia and decreased lymphocyte count
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MGC018 is a B7-H3 ADC drug under development by MacroGenics.
It is formed by anti-B7-H3 humanized IgG1 monoclonal antibody coupled with cleavable linker Duocarmycin (DUBA), with an average DAR of 2.
7
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DUBA is a DNA alkylating agent that targets the DNA minor groove and can cause DNA double-strand breaks
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At ESMO 2021, MacroGenics announced a phase I clinical trial of MGC018 in the treatment of advanced solid tumors (cohort expansion, NCT03729596), which enrolled 86 patients, including 40 with prostate cancer, 21 with non-small cell lung cancer, and 16 with triple-negative breast cancer.
and 9 melanoma patients
.
A total of 37 patients withdrew from the trial, including 25 with progressive disease (PD), 6 with AEs, 1 with physician opinion, and 1 with death
.
In terms of safety, 43 patients experienced grade 3 or higher TRAEs (50%), and common severe TRAEs included neutropenia (22.
1%) and thrombocytopenia (7%)
.
In terms of efficacy, among 32 evaluable patients, the objective response rate was 25% (8/32), all of which were partial responses, including 4 patients with prostate cancer and 4 patients with non-small cell lung cancer
.
Overall, MGC018 has good therapeutic prospects in prostate cancer and non-small cell lung cancer, but the safety is worthy of further exploration.
Currently, MacroGenics is further optimizing the starting dose of MGC018
.
Focusing on China, Bio-Tech's BAT8009 is a B7-H3 ADC drug, which was approved for clinical use on April 15, 2020.
The drug is a combination of recombinant humanized anti-B7-H3 antibody and DNA topoisomerase inhibitor.
It is coupled with a cleavable linker and has a bystander effect
.
(3) Orlotamab (MGD009), a dual-antibody drug, is a humanized, bispecific DART molecule developed by MacroGenics, which can recognize both CD3 and B7-H3, and kill B7-H3-expressing molecules through the relocation of T cells.
tumor cells
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DART technology is a patented technology of MacroGenics Company.
It is a heterodimeric antibody formed by the combination of two polypeptide chains.
First, the VL and VH of the variable region of one antibody and the VL of the variable region of the other antibody are separated by linker.
, VH sequences are linked to form scFv, and then two scFv fragments are co-expressed, and bispecific fragments are formed by the interaction between antibody VH and VL domain chains
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Compared with the BiTE platform, the DART platform possesses better structural and biological properties, including better stability and better redirection of the cytotoxic effects of T cells against malignant cells
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In 2018, Orlotamab was placed on a partial clinical hold by the FDA due to hepatic adverse events, and it was announced to remove the hold in January 2019
.
In recent years, the company has not disclosed the clinical progress of Orlotamab.
It is worth mentioning that there is no Orlotamab in the company's R&D pipeline, which may be related to adverse liver toxicity events
.
(4) CAR-T cell therapy TAA06 injection is a targeted B7-H3 CAR-T cell therapy developed by Boshengji Pharmaceutical Technology Co.
,
Ltd.
On March 21, 2022, Boshengji Pharmaceutical Technology Co.
, Ltd.
announced that TAA06 injection was granted orphan drug designation by the FDA for the treatment of neuroblastoma
.
In addition, scientists from Stanford University and Harvard University performed B7-H3 CAR-T cell therapy in a mouse model and observed that B7-H3 CAR-T could significantly inhibit the growth of tumors in mice and prolong the survival period of mice
.
03 Summary Although the molecular mechanism of B7-H3 is still unclear, as a potential immune checkpoint molecule, its tumor immunotherapy prospects have attracted much attention
.
MacroGenics is deeply engaged in the B7-H3 target.
The drugs under development involve monoclonal antibodies, dual antibodies and ADCs.
The clinical trials of dual antibody products have been suspended by the FDA due to hepatotoxicity, and they are currently hard to find in the company's R&D pipeline.

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The monoclonal antibody product enoblituzumab has good prospects in combination with PD-1 inhibitors, doubling the objective response rate in head and neck squamous cell carcinoma and non-small cell lung cancer
.
The global ADC leader Daiichi Sankyo also favors this target.
The DS-7300 follows the design of the Trop2 ADC product DS-1062
.
Focusing on China, Tianjing Bio’s license in enoblituzumab; Bio-Thera is fighting B7-H3 ADC again; Boshengji’s CAR-T cell therapy targeting B7-H3 has been granted orphan drug designation by the FDA
.
In general, the B7-H3 target is in a state of blooming as a whole.
Let us wait and see who will stand out
.