Patterns of Antibody Therapy For Breast Cancer

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Patterns of Antibody Therapy For Breast Cancer

According to statistics from the International Association for Research on Cancer,
approximately 685,000 people worldwide died of breast cancer in 2020. Among
female-related cancer deaths, breast cancer accounts for approximately 15.5%. And in
2020, approximately 2.3 million people worldwide were diagnosed with breast cancer,
which has surpassed lung cancer to become the number one killer of women's health.

However, what is gratifying is that from 2007 to 2016, the mortality rate of breast cancer
has been decreasing at a rate of 1.8% per year. This is mainly due to the advancement of
medical technology. The current treatment of breast cancer mainly includes surgery,
radiotherapy, chemotherapy, hormone therapy and targeted therapy. Among them,
targeted therapy not only provides patients with a variety of options, but also greatly
improves the survival of patients.

1. Patterns of antibody therapy for breast cancer

The antibodies currently approved or in clinical use for the treatment of breast cancer can
be divided into three categories:

1) Naked antibodies targeting tumor surface antigens

This type of antibody mainly blocks tumor cell growth related signal pathways by binding
to HER2 or other antigens on the tumor surface, thereby inhibiting tumor growth, or killing
tumor cells through antibody-mediated ADCC.

2) Antibody Drug Conjugates

This type of antibody also targets the antigen on the surface of tumor cells, but the
antibody is coupled with small molecule toxicants or radiopharmaceuticals. After the
antibody binds to the antigen on the tumor cell surface, it enters the tumor cell through
endocytosis, and release small molecule poison or radioactive drugs through lysosome or
enzyme, so as to kill the tumor cells.

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3) Immune checkpoint inhibitory antibodies represented by PD-1 and PD-L1
antibodies

These antibodies inhibit the inhibitory PD-1 or PD-L1 of the immune system, and then
stimulate the immune response of the body's immune system, and ultimately kill or inhibit
tumor cells through the immune system.

2. Monoclonal Antibodies & Bispecific Antibodies in breast
cancer therapy

Targeting HER2

HER2 is expressed in 15-20% of breast cancer patients, so this target is an ideal target for
breast cancer treatment. Currently, two monoclonal antibodies targeting HER2
(trastuzumab and pertuzumab) have been approved for the treatment of breast cancer,
targeting the fourth and second domains of HER2, respectively.

At the same time, there are currently several antibodies against HER2 under clinical
evaluation, such as Margetuximab, MCLA128 and ZW25.

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Margetuximab

Margetuximab is a monoclonal antibody targeting the fourth domain of HER2. Unlike
Trastuzumab, this antibody modifies Fc (F243L/R292P/Y300L/L235V/P396L) to enhance
antibody binding to CD16A, thereby increasing the ADCC effect mediated by the antibody,
and at the same time the antibody reduces the affinity for CD32B, thus enhancing the
body's immune response. The drug has been approved by the FDA in December 2020 for
the treatment of adult metastatic HER2-positive breast cancer in combination with

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chemotherapy.

MCLA 128

MCLA 128 is a bispecific antibody targeting HER2 and HER3. After the antibody binds to
HER3, the antibody can block the binding of NRG1 protein to HER3. HER2/HER3
dimerization can be blocked even at high NRG1 protein levels. Therefore, it can block the
activation of the downstream signals of HER2/HER3, thereby inhibiting the growth of
tumor cells. In addition, the antibody modified Fc to enhance the ADCC effect mediated by
the antibody, and further enhance the killing of tumor cells. The antibody is currently in 1/2
clinical trials.

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ZW25

ZW25 is a bispecific antibody developed based on Zymeworks' AzymetricTM platform. It
can simultaneously bind to two non-overlapping epitopes (second domain and fourth
domain) of HER2, which is called dual complementary binding. This unique design
produces multiple mechanisms of action, including dual HER2 signal blockade, increased
endocytosis of antibodies to increase the binding and removal of HER2 protein from the
cell surface, and effective effector functions. The antibody is currently in clinical phase 2
and was introduced by BeiGene in China.

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Antibodies that target other antigens

In addition to the HER2 target, there are other targets currently under development for the
treatment of breast cancer, such as VEGF, PRLR (prolactin receptor), Pobo1 receptor
and so on.

3. ADC for breast cancer treatment

Compared with naked antibodies, the ADC field has more targets for the treatment of
breast cancer.

In addition to HER2, there are glycoprotein non-metastatic, trophoblast cell surface
antigen, CA6 (sialylated MUC1), LIV-1 (a multiple transmembrane protein), and PTK7
(Protein tyrosine kinase 7), LAMP-1 (lysosomal surface-associated protein), P-cadherin (a
cell membrane surface glycoprotein) and ephrinA4 (a member of the PTKs family).

Currently, two ADC drugs targeting HER2 have been approved by FDA for marketing --
TDM-1 and DS-8201A.

TDM-1

Trastuzumab, the small molecule cytotoxin DM1 is a microtubule inhibitor. TDM1 targets
the fourth domain of the HER2 receptor, leading to intracellular release of cytotoxic
catabolites containing DM1 through receptor-mediated internalization and subsequent
lysosomal degradation. Binding of DM1 to tubulin disrupts the intracellular microtubule
network, leading to cell cycle arrest and apoptotic cell death.

In 2013, the FDA approved TDM1 for the treatment of HER2-positive metastatic breast
cancer patients who had previously received trastuzumab and taxane alone or in
combination. In 2019, the FDA approved TDM1 as an adjunctive therapy for
HER2-positive early-stage breast cancer patients with residual invasive disease after
neoadjuvant therapy with taxane and trastuzumab. Similar to TDM1, Medi-4276,
XMT-1522, and ARX788 are all ADC drugs targeting HER2, which carries microtubule
inhibitors, and are currently under clinical evaluation.

DS-8201a

DS-8201a is constructed from the humanized HER2 monoclonal antibody trastuzumab via
a peptide-based linker coupled to a new topoisomerase I inhibitor camptothecin derivative
(DX-8951 derivative DXd) . It binds to HER2 on the surface of tumor cells through

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trastuzumab, enters tumor cells through HER2-mediated endocytosis, and is
phagocytosed by intracellular lysosomes. Subsequently, the lysosomal enzyme cleaves
the polypeptide linker, releases the loaded DXd, inhibits the activity of topoisomerase I,
and then induces DNA damage and cell apoptosis, and exerts an effective anti-tumor
effect.

Sacituzumab govitecan

Sacituzumab govitecan is an ADC drug formed by coupling a humanized IgG1 antibody
targeting the TROP-2 antigen and the metabolically active product SN-38 of the
chemotherapeutic drug irinotecan (a topoisomerase I inhibitor). It was approved by the
FDA in April 2020 for the treatment of metastatic triple-negative breast cancer (TNBC) in
patients who have received at least two therapies. It is the first ADC drug targeting
TROP-2 that approved by FDA for the treatment of patients with metastatic triple-negative
breast cancer. Biopharma PEG supplies
product 2-((Azido-PEG8-carbamoyl)methoxy)acetic acid, which is a fragment
of Sacituzumab govitecan(IMMU-132).

TROP-2 is a cell surface glycoprotein encoded and expressed by the TACSTD2 gene. Its
expression in normal tissues is very low, and it is overexpressed in a variety of malignant
tumors. It mainly promotes tumor cell growth, proliferation and metastasis by regulating
calcium ion signal pathway, cyclin expression and reducing fibronectin adhesion. TROP2

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can also interact with β-catenin in the Wnt signaling cascade, and play a role in the
transcription of nuclear oncogenes and cell proliferation.

SAR566658

SAR566658 is an ADC drug targeting CA6 (tumor-associated glycosylated MUC-1). It is
composed of a huDS6 antibody that binds to CA6 and DM4 (Maytansine-derived
microtubule inhibitor). In a phase I clinical trial involving 114 patients, 60% of patients in
the 190 mg/m2 and 90 mg/m2 dose groups on the first and eighth days had tumor
regression. In the 150 mg/m2 and 120 mg/m2 dose groups in the biweekly administration
group, 35% of patients experienced tumor regression.

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In addition to the ADC drugs introduced above, there are currently many ADC
drugs targeting different targets of breast cancer in clinical trials, which will not be
described in detail here. See the table below for specific information.

4. Advances in the treatment of breast cancer with PD-1 and
PD-L1 antibodies

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PD-1 (CD279) is a member of the CD28 family, which mainly plays an
immunosuppressive role. It also plays an important role in the immune escape of tumor
cells.

PD-1 is expressed on a variety of immune cells, including NKT cells, B cells and DC cells.
The interaction of PD-1 and its ligand PD-L1 (CD274/B7-H1) can inhibit the proliferation
and survival of T lymphocytes, and can promote the programmed death of T cells in the
tumor microenvironment. Factors inhibiting PD-1 or PD-L1 can effectively stimulate the
body's immune response and inhibit or kill tumor cells through the immune system.

At present, a number of PD-1 and PD-L1 related antibodies have been approved for
marketing, and they have also achieved good efficacy in different indications. Their
research progress and efficacy in breast cancer are shown in the following table.

Conclusion

The development of antibody technology has brought great success to the treatment of
breast cancer. At present, there are mainly three types of antibody-related drugs that are
being clinically explored for the treatment of breast cancer.

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The first category is antibodies targeting tumor surface antigens, including monoclonal
antibodies such as trastuzumab and pertuzumab that have been approved for marketing,
and bispecific antibodies such as MCLA128 targeting Her2 and Her3 and ZW25 targeting
different domains of Her2.

The second category is ADC drugs that target tumor cell surface antigens. At present,
three ADC drugs have been approved for the treatment of breast cancer, two of which
target Her2 (TDM-1 and DS-8201a), and one targets TROP- 2 (Sacituzumab govitecan),
and there are many ADC drugs targeting other targets under clinical evaluation, such as
CA6, LIV-1, PTK7, LAMP-1, P-cadherin and ephrin A4.

The third category is an antibody that activates the body's immune system, PD-1 or PD-L1.
These antibodies use immune-related cells to kill tumor cells by activating the immune
system.

Of course, in addition to the above-mentioned antibody monotherapy for breast cancer,
there are currently a variety of combinations of drugs under exploration, including
trastuzumab and pertuzumab combined with small molecule drugs, PD-1 antibody
combined with paclitaxel and other drugs.

Therefore, the treatment of antibodies in the field of breast cancer can be described as a
hundred flowers blooming! We also hope that more and more treatment options will come
out to bring good news to breast cancer patients.

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As a worldwide leader of PEG linker, Biopharma PEG offers a wide array of
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References:
[1] A Review of Therapeutic Antibodies in Breast Cancer
[2] Novel antibody–drug conjugates for triple negative breast cancer
[3] A bifunctional fusion protein increases PRLR-positive breastcancer cell death in co-culture with
natural killer cells
[4] DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase IInhibitor, Demonstrates a
Promising Antitumor Efficacy with Differentiationfrom T-DM1

Related articles:

[1] Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
[2] ADC Drugs with New Targets Clinical Pipeline Review
[3] Progresses Of ADC Technology For Cancer Therapy
[4] The History Of ADC Drugs Development

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[5] History and Development of Antibody Drug Conjugates (ADCs)
[6] ADCs Against Cancer: Clinical Landscape and Challenges