Monoclonal Antibodies in Clinical Trials for Breast Cancer Treatment

Abstract

One of the most potent therapeutic and diagnostic agents in contemporary medicine is the monoclonal antibody (mAb). mAbs can perform a variety of tasks in breast cancer (BC), including identifying and delivering therapeutic medications to targets, preventing cell development, and suppressing immune system inhibitors including directly attacking cancer cells. mAbs are one of the most effective therapeutic options, particularly for HER2, but they have not been well studied for their use in treating other forms of BC, particularly triple negative breast tumors. Bispecific and trispecific mAbs have created new opportunities for more targeted specific efficacy, which has a positive impact on the viability of antigen specificity. They are more versatile and effective than other forms of treatment, emerging as most popular option for treating BC. However, mAbs have a limit in treatment due to certain adverse effects, including fever, shaking, exhaustion, headache, nausea, and vomiting, as well as rashes, bleeding, and difficulty breathing. To examine the current and prospective future capacities of mAbs with regard to the detection and treatment of BC, the present review highlights advantages and disadvantages of mAb approach.

Introduction to Monoclonal Antibodies and Breast Cancer

Monoclonal antibodies

Role of monoclonal antibodies in cancer

The multitasking monoclonal antibodies (mAbs) have various methods for destroying cancer cells. Some mAbs function by sabotaging the checkpoint system, which is a signaling system produced by the cancer cell.¹ Your immune system’s checkpoints prevent it from responding to invaders and unintentionally harming healthy tissue.² By putting checkpoint proteins on their surface to defend them from immune system attack, cancer cells can shut down the system.³ Some mAbs block these checkpoints, enabling T cells in your immune system to kill cancer cells that are their target.⁴

mAbs and their function in breast cancer

The development of mAbs that specifically target growth factor receptors has been a highly significant advancement in the treatment of breast cancer (BC) over the last decade.⁵ Conventional cancer therapies are generally indiscriminate and harmful to both healthy and malignant cells.⁶ To improve the success rates of treatment and reduce harm to healthy cells, researchers are currently working on the development of novel anticancer drugs that selectively focus on the molecular abnormalities present in tumor cells.⁷ Advancements in the comprehension of tumor pathobiology and molecular biology have facilitated the development of these specialized medications targeting BC.⁸ BC is among the various types of cancer that exhibit the presence of the human epidermal growth factor receptor (HER; erbB) family. These receptors possess tyrosine kinase activity.⁹ The vascular endothelial growth factor (VEGF) receptor has become a focus for treating BC due to its significant involvement in the formation and spread of tumors through angiogenesis.¹⁰ The primary offenders are antibodies that specifically target VEGF and the extracellular domain of erbBs.¹¹

Applications

Numerous diseases, including inflammatory, cancerous, autoimmune, and cardiovascular conditions, can be treated with them. Targeted specificity, which is their primary method of action, is one of the many important benefits that mAbs provide as therapeutic agents.¹² As a result, they have a reduced toxicity and side effect profile than many small molecule medicines, which frequently accompany them.¹³ Furthermore, because immunoglobulins have discrete subunit functionality, several immune system counterparts work in concert with other mAb components, such as the complement cascade that the Fc region of Immunoglobulins G (IgGs) initiates to destroy cells.¹⁴ Therefore, it is anticipated that the therapeutic potential of MAbs would increase as more immune-modulated capabilities are discovered in the upcoming years.¹⁵

Breast cancer

Breast tissue is where BC starts when cells change and proliferate out of control, creating a tumor. It may migrate to neighboring tissues and maybe to other body parts, where it may develop into other tumors.¹⁶ Metastasis is a prevalent phenomenon in many types of cancer. BC, which primarily affects women over 50, is the second most common malignancy in women after skin cancer.¹⁷ Although it is uncommon, men can have BC; in the United States, there are roughly 2600 instances each year or less than 1% of all cases.¹⁸ While transgender males are less at risk than cisgender women, transgender women are at higher risk than cisgender men.¹⁹

Etiology and risk factors

The development of BC is attributed to the abnormal division and rapid growth of breast cells. Age is a significant risk factor for BC, and the risk increases after reaching the age of 55.²⁰ Incidence of BC is significantly higher in females than in males. Genetic testing can identify that a specific defective gene, inherited from parents, is responsible for 5%–10% of breast tumors.²¹ Smoking, alcohol intake, and obesity are associated with an elevated risk of both initial development and recurrence of BC. Previous radiation therapy, especially targeting the head, neck, or chest, raises the likelihood of BC in women.²² Individuals who do hormone replacement therapy (HRT) have a higher likelihood of developing BC compared with those who do not use HRT.²³

There are multiple distinct forms of BC, which include infiltrating ductal carcinoma, ductal carcinoma in situ, infiltrating lobular carcinoma, lobular carcinoma in situ, triple negative BC (TNBC), and inflammatory BC.²⁴

Stages

The staging of cancer is used to describe the extent or severity of the disease in the body. The dimensions, position, and magnitude of the tumor, along with the presence of metastasis, all factor into this determination. The main stages of BC are as follows.²⁵

Stage 0 – The illness has no invasiveness. This indicates that it has not escaped the breast ducts.²⁶

Stage I – The adjacent breast tissue has become infected with cancerous cells.²⁷

Stage II – The tumor is either <2 cm in size and has spread to the lymph nodes under the arms or it is >5 cm in size but has not migrated to the lymph nodes.²⁸ During this phase, tumors have the potential to affect or not affect the nearby lymph nodes and can vary in size from 2 to 5 cm.²⁹

Stage III – Indicates that the cancer has metastasized beyond its primary location.³⁰ While there is a possibility that it has spread to nearby lymph nodes and tissue, it has not yet metastasized to distant organs.³¹ Stage III BC is commonly known as locally advanced.³²

Stage IV – Refers to the advanced stage of cancer where it has spread beyond the breast to other parts of the body such as the bones, liver, lungs, or brain. Metastatic BC (MBC) is a synonym for stage Intravenous (IV) BC.³³

FIG. 1.

mAbs and mAbs equipped with chemotherapeutics. mAbs, monoclonal antibodies.

FIG. 2.

Production of mAbs. mAbs, monoclonal antibodies.

FIG. 3.

Applications of mAbs in breast cancer. mAbs, monoclonal antibodies.

Overview of clinical trials investigating mAbs

The table describes the mAbs which were undergoing clinical trials to investigate their applications in BC treatment (Fig. 4). It also includes the combination drugs along with mAbs, which enhance the therapeutic outcomes of respective mAbs.³⁴ Still numerous clinical trials have been going on to establish and increase the benefits of mAbs in BC therapy. Table 1 gives in detail an overview of clinical trials investigating mAbs.³⁵

FIG. 4.

Types of monoclonal antibodies.

Table 1.

Overview of Clinical Trials Investigating Monoclonal Antibodies

S. No	Drug name	Combination drugs	Phase/status	NCT No.
1	Inetetamab Toripalimab	Albumin-Bound Paclitaxel	IV	NCT05291910
2	Cirmtuzumab	Paclitaxel	I	NCT02776917
3	HX008	Cisplatin Gemcitabine	I, II	NCT04750382
4	Trastuzumab Pertuzumab	PUMVC3-IGFBP2-HER2-IGF-1R Plasmid DNA vaccine. Paclitaxel	II	NCT04329065
5	Trastuzumab Pertuzumab	Docetaxel/Epirubicin/Cyclophosphamide/Carboplatin. Traditional herbal medicine	II	NCT05483439
6	HX008 Trastuzumab	Niraparib Pyrrolitinib	II/Completed	NCT04508803
7	Pertuzumab Trastuzumab	Copanlisib	I, II	NCT04108858
8	Inetetamab	Cyclophosphamide Metronomic chemotherapy+AI	II	NCT04941885
9	Pembrolizumab	Paclitaxel	II	NCT04946227
10	Trastuzumab	Pyrotinib	III	NCT04973319
11	Durvalumab	Capivasertib Ceralasertib Olaparib Selumetinib	II	NCT03801369
12	Inetetamab	Pyrotinib Capecitabine Gemcitabine Vinorelbine	II	NCT04681911
13	Trastuzumab Pertuzumab	Cyclophosphamide	I	NCT05385705
14	Panitumumab Pembrolizumab	Carbonation Cyclophosphamide Doxorubicin Paclitaxel	II	NCT03606967
15	Trastuzumab	BI-1607	I, II	NCT05555251
16	Durvalumab Tremelimumab	Gemcitabine hydrochloride Nab-Paclitaxel Poly ICLC	II	NCT03606967
17	Pembrolizumab	Tamoxifen Vorinostat	II	NCT04190056
18	Pembrolizumab	Ivermectin	I, II	NCT05318469
19	Pembrolizumab	HMBD-002	I	NCT05082610
20	Nadunolimab	Carboplatin Gemcitabine	I, II	NCT05181462
21	Atezolizumab	Eribulin Cobimetinib	II	NCT03202316
22	Pembrolizumab	Ruxolitinib phosphate	I/Completed	NCT03012230
23	Pertuzumab Trastuzumab	Carboplatin Docetaxel Fulvestrant Ribociclib	I, II	NCT05319873
24	Trastuzumab	Placebo	III	NCT01785420
25	Pembrolizumab	Carboplatin Transferring receptor-targeted liposomal p53 cDNA	I	NCT05093387
26	Retifanlimab	Pelareorep	II	NCT04445844
27	Trastuzumab	Anastrozole Deruxtecan	II	NCT04553770
28	Avelumab Utomilumab Sacituzumab	Binimetinib Liposomal doxorubicin Govitecan	II	NCT03971409
29	Sacituzumab	Govitecan	II	NCT04647916
30	Trastuzumab	Emtansine Placebo Tucatinib	III	NCT04457596
31	Pembrolizumab	Imprime PGG	II/Completed	NCT05159778
32	Pertuzumab Trastuzumab	Docetaxel QL1209	III	NCT04029846
33	Avelumab	Palbociclib	I	NCT04360941
34	Atezolizumab Bevacizumab	Gemcitabine Carboplatin	II	NCT04739670
35	Bevacizumab	Apatinib mesylate Albumin-bound paclitaxel	II	NCT05192798
36	Trastuzumab Pertuzumab	Nab-paclitaxel Pyrotinib Capecitabine T-DM1 Everolimus	III	NCT05429684
37	Trastuzumab	Alpha-tocopheryloxyacetic acid	I	NCT04120246
38	Avelumab Pembrolizumab Invaluable Atezolizumab	Cyclophosphamide Fludarabine IL-2 FT536	I	NCT05395052
39	Trastuzumab Pertuzumab	Emtansine	II	NCT04680442
40	Trastuzumab Pertuzumab	ARX88 Pyrotinib maleate Docetaxel	II, III	NCT05426486
41	Panitumumab	Carboplatin Paclitaxel	II	NCT02593175
42	Atezolizumab	KY1044	I, II	NCT03829501
43	Pertuzumab Trastuzumab	Placebo Sargramostim Emtansine	II	NCT04197687
44	Trastuzumab	Deruxtecan Copper Cu64-DOTA	IV	NCT05376878
45	Atezolizumab	Cabozantinib-s-malate Nab-paclitaxel	I	NCT05092373
46	Pembrolizumab	ONC-392	I, II	NCT04140526
47	Dostarlimab	Niraparib	I	NCT04673448
48	Trastuzumab	Duocarmazine Paclitaxel	I	NCT04602117
49	Pembrolizumab	XmAb(R)808	I	NCT05585034
50	Pembrolizumab	Cyclophosphamide Sargramostim	I	NCT05269381
51	Trastuzumab	Deruxtecan Ceralasertib	I	NCT04704661
52	Nivolumab	Cabozantinib-s-malate	I	NCT04514484
53	Pembrolizumab	ONCR-177	I	NCT04348916
54	Atezolizumab	BDB001	II	NCT03915678
55	Trastuzumab	Anastrozole Exemestane FASN Inhibitor TVB-2640 Fulvestrant	II	NCT03179904
56	Bevacizumab Pembrolizumab	ZN-c3	I	NCT05431582
57	Ipilimumab	XmAb(R)23104	I/Completed	NCT03752398
58	Pertuzumab Trastuzumab	Docetaxel Nab-paclitaxel Paclitaxel Emtansine	II	NCT04266249
59	Daratumumab Nivolumab Obinutuzumab Pembrolizumab Rituximab Trastuzumab	Belinostat Carfilzomib Copanlisib hydrochloride Fludeoxyglucose F-18 Gemcitabine hydrochloride Romidepsin	I	NCT03432741
60	Atezolizumab	Carbo/cyclo+paclitaxel	II	NCT01898117
61	Pembrolizumab	ATRC-101 Permeated liposomal doxorubicin (PLD)	I	NCT04244552
62	Durvalumab	AZD8701	I	NCT04504669
63	Atezolizumab	Carboplatin Paclitaxel Epirubicin	II	NCT04770272
64	Nivolumab	BDC-1001	I, II	NCT04278144
65	Trastuzumab	Pyrotinib	III	NCT04733319
66	Trastuzumab	Cyclophosphamide Doxorubicin hydrochloride Paclitaxel	II	NCT01750073
67	Bevacizumab	Carboplatin Paclitaxel-albumin stabilized	II/Completed	NCT00618657
68	Atezolizumab	Carboplatin	II	NCT03206203
69	Trastuzumab	Cyclophosphamide Docetaxel Doxorubicin	III	NCT01275677
70	Pembrolizumab	Ruxolitinib phosphate	I/Completed	NCT03012230
71	Trastuzumab	AMG479	I, II	NCT01479179
72	Trastuzumab	Docetaxel Carboplatin Ribociclib	I, II	NCT0531987
73	Trastuzumab	Vinorelbine ditartrate	I/Completed	NCT00014430
74	Atezolizumab	Carboplatin Paclitaxel	II/Completed	NCT02883062
75	Bevacizumab	Trastuzumab Carboplatin Paclitaxel	III	NCT00520975
76	Durvalumab	Trastuzumab Pertuzumab	II	NCT03820144
77	Cirmtuzumab	Paclitaxel	I/Completed	NCT02776917
78	HX008	Cisplatin Gemcitabine	I/II	NCT04750382
79	Toripalimab	Guaifenesin	I	NCT03251313
80	Bevacizumab	Letrozole Tamoxifen citrate	III	NCT00601900
81	Durvalumab	Tremelimumab	I	NCT03132460
82	Trastuzumab	Cyclophosphamide Paclitaxel	II	NCT02654119
83	Trastuzumab	Lapatinib ditosylate Paclitaxel	III	NCT00770809
84	Trastuzumab	Lapatinib ditosylate	III	NCT01104571
85	Atezolizumab	Capecitabine Carboplatin Ipatasertib	I,II/Completed	NCT03853707
86	Atezolizumab	Olaparib	II	NCT02849496
87	Trastuzumab	Paclitaxel Cyclophosphamide Doxorubicin hydrochloride	Not applicable	NCT01897441
88	Atezolizumab	Nab-Paclitaxel	III	NCT02530489
89	Panitumumab	Carboplatin Paclitaxel	II	NCT02876107
90	Atezolizumab	Paclitaxel Docetaxel	III	NCT03199885
91	Trastuzumab	Cyclophosphamide Doxorubicin hydrochloride Paclitaxel	II/completed	NCT00618657
92	Bevacizumab	Trastuzumab Paclitaxel Carboplatin	II/completed	NCT00618657
93	Atezolizumab	Carboplatin	II	NCT03206203
94	Trastuzumab	Cyclophosphamide Docetaxel Doxorubicin	III	NCT01275677
95	Oleclumab	Paclitaxel Carboplatin	I, II	NCT03616886
96	Atezolizumab	Paclitaxel Carboplatin	II/completed	NCT02883062
97	Trastuzumab	Lapatinib	II	NCT01273611
98	Pembrolizumab	Celecoxib Rintatolimod	Early phase-1 Completed	NCT03599453
99	Pembrolizumab	Radiation therapy	III	NCT02954874
100	Avelumab	Talazoparib	I, II	NCT03964532
101	Pembrolizumab	Binimetinib	I, II/completed	NCT03106415
102	Pembrolizumab	Enobosarm	II/completed	NCT02971761
103	Mirvetuximab	Gemcitabine Gemcitabine hydrochloride Soravtansine	I	NCT02996825
104	Nivolumab	Romidepsin Cisplatin	I, II	NCT02393794
105	Durvalumab	PVX-410 Hiltonol	I	NCT02826434
106	Bevacizumab	Cyclophosphamide Doxorubicin hydrochloride Paclitaxel	III	NCT00433511
107	Nivolumab	Ipilimumab Entinostat	I	NCT02453620
108	Pertuzumab Trastuzumab	Paclitaxel	I, II/completed	NCT03112590
109	Pertuzumab	Paclitaxel	I	NCT03716180
110	Atezolizumab	Ipatasertib Paclitaxel	III/completed	NCT04177108
111	Trastuzumab	Vinorelbine MCLA-128	II/completed	NCT03321981
112	Atezolizumab Bevacizumab	Nab-Paclitaxel	II	NCT03961698
113	Trastuzumab	Neratinib Loperamide	II/completed	NCT03094052
114	Durvalumab	Neoantigen DNA Vaccine	I	NCT03199040
115	Bevacizumab	Atezolizumab Cobimetinib	II/Completed	NCT03395899
116	Leronlimab	Carboplatin	I, II	NCT03838367

The detailed description of the data collected is as follows:

Trastuzumab: Herceptin is a mAb that acts against HER2+ receptors. Here a total of about 41 clinical trials in which trastuzumab has been used are mentioned.³⁶ In 39 trials, it is used as a main drug, and in other 3 trails it is tested as a combination drug. Thus, it is concluded that trastuzumab is the most widely used for the clinical trials under the NCT numbers—NCT04329065, NCT05483439, NCT04508803, NCT04266249, etc.—and in the BC treatment.³⁷

Pembrolizumab: is classified as an immune checkpoint inhibitor. It functions by attaching to the Programmed Cell Death Protein 1 (PD-1) protein located on certain T cells, preventing cancer cells from inhibiting the immune system.³⁸ It is primarily utilized in the management of triple negative, locally recurrent, or secondary BC. More than 20 clinical trials have been conducted with pembrolizumab as the primary drug, with the following NCT numbers: NCT04946227, NCT03606967, NCT04190056, NCT05395052, NCT03599453, and others.³⁹

Pertuzumab: is a medication that is administered alongside trastuzumab and docetaxel to treat HER2+ BC.⁴⁰ A total of 19 clinical trials involving pertuzumab have been identified, with its combination therapy being referenced by the NCT numbers: NCT03716180, NCT03112590, NCT04266249, NCT04197687, and others.⁴¹

Atezolizumab: is classified as an immune checkpoint inhibitor. By inhibiting immune checkpoint proteins such as Programmed Cell Death Ligand 1 (PD-L1) and PD-1, it removes the inhibitory signals on the immune system, hence augmenting the capacity of immune cells to locate and eliminate cancer cells. A total of 18 clinical studies have been done to date under the NCT numbers NCT03202316, NCT04739670, NCT05395052, NCT05092373, NCT03915678, and others.⁴²

Bevacizumab: is a medication that inhibits the formation of blood vessels. It is sometimes used off-label to treat advanced stage or MBC. It functions by inhibiting the formation of new blood vessels that are essential for the growth and functioning of cancer cells.⁴³ A total of 10 clinical trials, identified by their respective NCT numbers (NCT04739670, NCT05192798, NCT05431582, NCT00618657, etc.), were collected.⁴⁴

Durvalumab: is a medication that enhances the ability of immune cells to eliminate cancer cells by binding to the PD-L1 protein. It is used in the treatment of several cancer types, including BC. A total of seven clinical trials with the NCT numbers NCT04770272, NCT03820144, NCT03132460, and others were gathered and assessed.⁴⁵

Leronlimab: is a humanized mAb that specifically targets the CCR5 receptor present on T cells in the human immune system. It is currently under investigation as a potential therapeutic approach for treating TNBC.⁴⁶ It is the sole medication used in a solitary clinical trial registered under the NCT number NCT03838367.⁴⁷

Along with the abovementioned major drugs, many other various types of mAbs such as nivolumab, avelumab, oleclumab, panitumumab, toripalimab, and so on have been used in different clinical trials with different chemotherapy combinational agents.⁴⁸

Combinational drugs: A wide range of chemotherapy and radiation therapy has been used as a combination therapy in different clinical trials as mentioned in the table.⁴⁹ The drugs like paclitaxel, docetaxel, cyclophosphamide, and carboplatin are the major drugs that have been repeatedly used as the combinational agents.⁵⁰

Completed clinical trials data

NCT04508803: There are numerous studies being conducted on anti-PD-1/L1 mAbs for BC, and several anti-PD-1/L1 mAbs have been approved for the treatment of various advanced malignancies worldwide.⁵¹ For the first-line therapy of advanced TNBC, the combination gemcitabine and cisplatin (GP) regimen HX008 (Taizhou Hanzhong Biomedical Co., Ltd., China) has demonstrated good success.⁵² Conversely, Human Resource Development (HRD) as the target of PARP inhibitor therapy has a wide range of potential applications in the treatment of BC.⁵³ In patients with HRD tumors, Poly(ADP-ribose) polymerase inhibitors (PARPi) can obstruct DNA damage repair (DDR), accumulate DNA damage, and encourage tumor cell apoptosis.⁵⁴ A number of PARPi, including olaparib, rucaparib, niraparib, talazoparib, and veliparib, have received approval globally for the treatment of breast and/or ovarian cancer.⁵⁵ It is theoretically possible for PARPi and anti-PD-1 mAb to work in concert.⁵⁶ To treat patients with MBC who have pathogenic or suspected pathogenic germline mutations in the DDR gene (BRCA1/2, PALB2, CHEK2, ATM, ATR, BAP1, BARD1, BLM, BRIP1, CHEK1, CDK12, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, NBN, Phosphatase and Tensin Homolog (PTEN), RAD50, RAD51C, RAD51D, WRN), HX008 in conjunction with niraparib is intended to treat these patients.⁵⁷

NCT03012230: Patients with stage IV TNBC that has progressed to other parts of their body are being treated in this phase I trial to determine the optimal dosage and adverse effects of ruxolitinib phosphate when combined with pembrolizumab.⁵⁸ mAbs, such as pembrolizumab, can be used in immunotherapy to help the body’s immune system to fight cancer and stop tumor cells from proliferating and spreading.⁵⁹ Ruxolitinib phosphate may inhibit some of the enzymes required for tumor cell proliferation, hence halting tumor cell growth.⁶⁰ To treat individuals with stage IV TNBC, pembrolizumab and ruxolitinib phosphate may be administered in combination.⁶¹

NCT05159778: Determining the overall response rate (ORR) per RECIST v1.1 after treatment with imprime PGG + pembrolizumab in patients with Estrogen Receptor/Progesterone Receptor (ER/PR)+/HER2(-) MBC who have advanced through previous hormone therapy with at least one CDK4/6 inhibitor and up to two subsequent chemotherapy treatments is the main goal of this Phase 2 Simon 2-Stage study.⁶² Patients’ baseline levels of anti-β glucan antibody (ABA), which are tested in peripheral blood, will be checked.⁶³ Patients who meet all other Inclusion/Exclusion (I/E) requirements and have an ABA of 20 mcg/mL or higher will be enrolled.⁶⁴ There will be 47 individuals in the trial, 23 of whom will be in Stage 1. The trial will move on to Stage 2 if four or more patients in Stage 1 show an objective response after 12 weeks of treatment.⁶⁵ Stage 2 will involve the enrolment of 24 patients, for a total population of 47. A study is considered successful if 10 patients exhibit objective responses overall.⁶⁶

NCT03752398: In this Phase 1 multiple-dose, ascending dose escalation study, XmAb23104’s Maximum Tolerated Dose/Recommended Dose (MTD/RD) and regimen are defined; safety and tolerability are described.⁶⁷ Pharmacokinetics (PK) and immunogenicity are evaluated, and the antitumor activity of XmAb23104 monotherapy and combination therapy with ipilimumab is preliminarily evaluated in subjects with specific advanced solid tumors.⁶⁸

NCT00618657: Patients with stage I–III BC are being treated in this phase II study to examine the adverse effects and effectiveness of a formulation of carboplatin and paclitaxel albumin-stabilized nanoparticles when combined with bevacizumab or trastuzumab before surgery.⁶⁹ Chemotherapy drugs, such carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, prohibit tumor cells from growing in two ways as follows: either by killing the cells or by preventing them from making new ones.⁷⁰ Tumor growth can be inhibited by mAbs such as trastuzumab and bevacizumab in several ways. Some stop the growth and spread of tumor cells.⁷¹ Others locate tumor cells and contribute to their destruction or deliver compounds that kill tumors for them.⁷² Combination chemotherapy and mAb therapy may help shrink the tumor and minimize the quantity of healthy tissue that must be removed before surgery.⁷³

NCT03012230: In this phase I trial, individuals with stage IV TNBC that has progressed to other parts of their body are treated to determine the optimal dosage and adverse effects of ruxolitinib phosphate when combined with pembrolizumab.⁷⁴ mAb immunotherapy, like that of pembrolizumab, may aid the body’s immune system in combating the disease and may prevent tumor cells from proliferating and spreading.⁷⁵ Because ruxolitinib phosphate inhibits some of the enzymes required for cell growth, it may prevent the growth of tumor cells. Pembrolizumab and ruxolitinib phosphate may be more effective when administered simultaneously to patients with stage IV TNBC.⁶¹

NCT00014430: Chemotherapy drugs hinder tumor cells from dividing in a variety of ways, causing them to either stop growing or die.⁷⁶ mAbs, such as trastuzumab, can find tumor cells and either kill them or give them molecules that destroy tumors without damaging healthy cells.¹¹ Vinorelbine with trastuzumab is used in a phase I trial to examine its efficacy in treating patients with metastatic or resistant BC.⁷⁷

NCT02883062: The effectiveness of carboplatin and paclitaxel, with or without atezolizumab before surgery, in treating patients with newly diagnosed stage II–III TNBC is being investigated in this phase II trial.⁷⁸ mAbs, like atezolizumab, can be used in immunotherapy to help the body’s immune system fight cancer and prevent tumor cells from proliferating and spreading.⁷⁹ Chemotherapy drugs such as carboplatin and paclitaxel do this in a variety of methods, by killing the tumor cells, preventing them from proliferating, or preventing them from spreading.⁸⁰ By administering carboplatin and paclitaxel, either with or without atezolizumab, before surgery, the tumor may shrink and less normal tissue may need to be removed.⁸¹

NCT02776917: This pilot phase 1 b trial is designed to investigate the safety and side effects of paclitaxel plus the receptor-tyrosine-kinase like orphan receptor 1 (ROR1)-targeting mAb cirmtuzumab in patients with HER2 negative, MBC.⁸² The drug class known as mAbs includes cerctuzumab. The target of this drug is the ROR1 protein found on the surface of BC cells. Cerctuzumab stops BC cells from proliferating and surviving in laboratory tests. Rarely do healthy cells express ROR1. In the United States, cerctuzumab has not been approved by the Food and Drug Administration (FDA) and is considered an experimental drug.⁸³

NCT03853707: This phase I trial examines the optimal dosage of ipatasertib and its efficacy in treating patients with TNBC that has metastasized (spread to other parts of the body) when combined with carboplatin and/or paclitaxel.⁸⁴ By inhibiting some of the enzymes required for cell growth, ipatasertib may prevent the growth of tumor cells.⁸⁵ Chemotherapy drugs such as capecitabine, paclitaxel, and carboplatin act in the following three different ways to stop tumor cells from growing: by killing the cells, preventing them from dividing, or preventing them from spreading.⁷⁶ mAb immunotherapy, like that of atezolizumab, may aid the body’s immune system in combating the disease and may prevent tumor cells from proliferating and spreading.⁷⁹ For patients with TNBC, it is currently unknown if ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab will be more effective.⁸⁶

NCT03106415: To treat patients with TNBC that has metastasized (spread to other parts of the body), this phase I/II trial investigates the optimal dosage of pembrolizumab and binimetinib, as well as how well they perform when administered simultaneously.⁶¹ Pembrolizumab and other mAbs used in immunotherapy may aid the body’s immune system in combating the disease and may prevent tumor cells from proliferating and spreading.⁸⁷ By inhibiting some of the enzymes required for cell growth, binimetinib may prevent the growth of tumor cells. Patients with TNBC may respond better to pembrolizumab with binimetinib.⁸⁸

NCT03112590: The aim of this research is to assess the safety and determine the ideal dosage for individuals with HER2-positive BC who receive the combination of interferon-gamma (IFN-γ), paclitaxel, trastuzumab, and pertuzumab.⁸⁹ The effects of IFN-γ with paclitaxel, trastuzumab, and pertuzumab, particularly its impact on this particular cancer type, will also be examined in this study.⁹⁰ The biologically produced protein known as IFN-γ is comparable to a naturally occurring protein produced by the body. Immune cells in the body create IFN-γ, which aids in preventing dangerous infections.⁹¹

NCT04177108: Ipatasertib in Combination with Paclitaxel and Atezolizumab as a Treatment for Patients with Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer: A Phase III, Double-blind, Placebo-controlled, Randomized Study.⁹²

NCT03321981: To assess the effectiveness of MCLA-128-based combinations, a multicenter, worldwide, phase 2 open-label trial will be conducted. Cohort 1 will assess two of the three combo treatments, whereas cohort 2 will evaluate one.⁹³ Two groups of people with MBC are treated with MCLA-128 (zenocutuzumab) in combination as follows: Cohort 1 is HER2-positive/amplified, and Cohort 2 is estrogen receptor-positive/low HER2 expression.⁹⁴ In Cohort 1, two treatment combinations—the doublet and triplet—will be assessed. At first, trastuzumab and zenocutuzumab are administered together in a doublet. In tandem with the doublet’s efficacy expansion, MCLA-128 is administered in combination with trastuzumab and vinorelbine in the triplet once the doublet’s safety has been evaluated in four to six patients.⁹⁵ An initial safety run-in is followed by a cohort efficacy expansion for both the doublet and triplet combinations. The doublet and triplet each include up to 40 participants who are evaluated for efficacy.⁹⁶ Zenocutuzumab is used in Cohort 2 in conjunction with the same prior endocrine medication that has been shown to cause progressive disease on radiological imaging. The Cohort 2 comprises a maximum of 40 individuals who are eligible for efficacy evaluation.⁹⁷

NCT03094052: This phase II trial examines the frequency and severity of diarrhea in individuals receiving trastuzumab and neratinib for stage II–IIIC HER2-positive BC.⁹⁸ Because it binds to particular molecules (receptors) on the surface of cancer cells called HER2 receptors, trastuzumab is a type of targeted therapy.⁹⁹ The body’s immune system may flag the cancer cell for death when trastuzumab binds to HER2 receptors, blocking the signals that instruct the cells to proliferate.¹⁰⁰ By inhibiting some of the enzymes required for cell growth, neratinib may prevent the growth of tumor cells. Patients with stage II–IIIC HER2-positive BC may respond better to trastuzumab and neratinib.¹⁰¹

NCT03395899: To assess the impact of immunotherapy-based treatment combinations in women with untreated, histologically confirmed, operable, ER+, HER2-negative BC, ECLIPSE is an international, open label, window of opportunity phase II trial.¹⁰² As new medicines become available, the research can be adjusted to add new treatment arms or change the patient group, for example, based on biomarker status. We will only try combinations with sufficient safety data.¹⁰³ Participants in the trial will be both luminal B and non-luminal B, regardless of their PD-L1 status; however, the proportion of patients with non-luminal B tumors will be limited to 50% of the study population.¹⁰⁴ The PAM50 assay will be used to characterize luminal B tumors, which will also be defined as high Ki67 (≥20%) and/or histological grade 3. The remaining varieties will all be classified as non-luminal B.¹⁰⁵

Efficacy of mAbs in treating BC

Trastuzumab is an essential component of the initial treatment for HER2-positive MBC. The clinical landscape may evolve due to the introduction of novel anti-HER2 therapeutics.¹⁰⁶ Similar response rates were observed with capecitabine combined with lapatinib (48%), continuing trastuzumab along capecitabine (48%), pertuzumab in conjunction with trastuzumab (24%), and neratinib (24%).¹⁰⁷ Trastuzumab emtansine (T-DM1) exhibited a response rate ranging from 26% to 64%. Various HER2-targeted therapies can provide additive or synergistic effects, improving outcomes (Fig. 5).¹⁰⁸ Patients with HER2-positive MBC who are administered trastuzumab often experience the development of brain metastases.¹⁰⁹ Three ideas elucidate this phenomenon as follows: The disease exhibits a pronounced tropism for the central nervous system (CNS) and demonstrates a more aggressive behavior; trastuzumab enhances patient survival and leads to brain metastases, which are generally a late manifestation of the disease; nevertheless, it does not penetrate the intact blood–brain barrier.^109,110 Trastuzumab did not seem to increase the incidence of brain metastases, based on data from clinical studies. No recognized prospective trials have evaluated trastuzumab in MBC patients with brain metastases.¹¹¹ Retrospective investigations have shown that patients with HER2-positive disease who received trastuzumab treatment experienced a longer time to develop CNS metastases and improved survival compared with those who did not receive the medication.¹¹² The management of systemic extracranial disease demonstrated that trastuzumab enhanced the prognosis of CNS metastases.¹¹³

FIG. 5.

Various classes of drugs used alone or in combination in breast cancers.

Immune efficacy

A 185-kDa transmembrane tyrosine kinase protein called HER2 (Her-2/neu, c-erbB-2) increases the aggressiveness of breast tumors (BCs).¹¹⁴ Of the initial breast tumors in humans, 15%–20% overexpress HER2, which is linked to decreased disease-free and overall survival (DFS) rates. For all phases of HER2-positive BC, trastuzumab combined with chemotherapy is an effective treatment.¹¹⁵ Other anti-HER2 mAbs have been effective in treating patients with HER2-positive tumors, either alone or in conjunction with trastuzumab.⁹³

In the integrated system of antitumor host defense, several cells and molecules work collaboratively, including innate and adaptive immune responses.¹¹⁶ Innate immunity refers to the capacity of natural killer (NK) cells, monocytes, and neutrophils to recognize and eliminate tumor cells independent of antigens.¹¹⁷ T and B lymphocytes that are specific for BC antigens, such as HER2, may be able to recognize and eliminate tumor cells. Evasion of innate and adaptive immunity is considered crucial for the progression and propagation of BC.¹¹⁸ The anticancer effects of mAbs may also be significantly influenced by innate and adaptive immunity, according to mounting evidence.¹¹⁹

Many human tissues contain hyaluronan, an extracellular glycosaminoglycan, and a variety of solid tumors in humans accumulate hyaluronic acid (HA). To construct a complex network inside the extracellular matrix, HA noncovalently associates with the N-terminal globular domains of proteoglycans such as aggrecan or versican, along with additional hyaladherins or hyalectans.¹²⁰ The buildup of HA in tumors is linked to malignancy and indicates a more aggressive form of the disease.¹²¹ Compression of blood vessels, an increase in interstitial fluid pressure, and impaired perfusion are all effects of elevated HA levels in tumors, sometimes in conjunction with collagen.¹²² In preclinical animal models, the removal of HA from solid tumors characterized by high-HA tumor microenvironments (TMEs) mitigates these physiological effects, resulting in tumor vasculature reperfusion, enhanced accumulation of chemotherapeutic agents, and suppression of tumor growth.¹²³ Malignant cells may also be protected from immune cell monitoring by the pericellular matrix with high HA content. The tumor stromal compartment’s pro-tumorigenic effect is further enhanced by its high HA concentration.¹²⁴

Targeted mAb

Targeted mAb therapies have lately achieved significant advancements in response and survival rates with less toxicity, solidifying mAbs as an integral element of the anticancer toolbox.¹²⁵ BC, gastric cancer, colon cancer, and more solid tumors are sanctioned indications for the anticancer agents trastuzumab (p185HER2) and cetuximab Epidermal Growth Factor Receptor (EGFR).¹²⁶ When HER2 or EGFR expression is increased in human malignancies, trastuzumab or cetuximab, respectively, limits tumor growth. Cetuximab and trastuzumab have had positive clinical results.¹²⁷ Previous descriptions of these mAb resistance mechanisms include a wide range of topics. Recently, the tumor Extracellular Matrix (ECM’s) possible contribution to treatment resistance has come to light.¹²⁸ Antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism of efficacy for mAb therapies (Fig. 3).¹²⁹ While the therapeutic antibody binds to antigens on the tumor cell surface, the Fc region of the antibody is recognized by the immune cell surface FcIIIA (CD16) receptor.¹³⁰ And the target tumor cell is subsequently eliminated by immune cells, particularly NK cells.¹³¹ ADCC plays a vital effector role in mAb-based therapy by directly eliminating target tumor cells, which may lead to tumor antigen presentation and the activation of tumor antigen-specific T cell responses.¹³²

Safety and tolerability of mAbs in BC

Safety

Highly targeted medicines with less toxicity include mAbs. mAbs not only cause the immediate killing of cancer cells but also immune activation and tumor cell toxicity.¹³³ mAbs have drawbacks, including their size, which may make it difficult for them to penetrate tumors, the expression of heterogeneous antigens, and the production of tumor antigens in normal cells.¹³⁴ There are numerous anti-HER mAbs being developed to treat various malignancies.¹³⁵

In 1975, Köhler and Milstein published their fundamental work on the generation of mouse mAbs utilizing the hybridoma approach (Fig. 2).¹³⁶ Since then, technological developments have enabled the transition from mouse to humanized and fully human mAbs, with fewer potentially immunogenic animal components. As a result, mAbs have achieved significant clinical success.¹³⁷

Since the United States Food and Drug Administration (USFDA) approved the first mAb in 1986, more than 30 years have passed, and antibody engineering has undergone significant change.¹³⁸ Because of their excellent specificity, current antibody medications have fewer and fewer side effects. Therapeutic antibodies have thus emerged as the most common type of novel medications created in recent years.¹³⁹ The USFDA has approved 79 therapeutic mAbs, including 30 mAbs for the treatment of cancer, out of 570 therapeutic mAbs that have been investigated in clinical trials, according to 2019 statistics.¹⁴⁰ The USFDA has approved 150 mAbs to date, with 151 undergoing clinical testing (Table 2).¹⁴¹

Table 2.

FDA Approved Monoclonal Antibodies (2020–24)

S. No	(Marketed)FDA approved	Indication	Target & MOA	Approval date
1	Zolbetuximab-clzb	Gastric or gastroesophageal junction adenocarcinoma	Bind to the transmembrane protein claudin 18.2 (CLDN18.2)	10/18/2024
2	Marstacimab-hncq	Reduce bleeding episodes related to hemophilia A or B	Tissue factor pathway inhibitor (TFPI) antagonist	10/11/2024
3	Lebrikizumab-lbkz	Moderate-to-severe atopic dermatitis	Interleukin-13 antagonist	09/13/2024
4	Axatilimab-csfr	Chronic graft-versus-host disease (cGVHD)	CSF-1R	08/14/2024
5	Nemolizumab-ilto	Prurigo nodularis	Interleukin-31 receptor	08/12/2024
6	Bevacizumab-tnjn	mCRC NSCLC GB RCC OC	VEGF & antagonist	12/06/2023
7	Ustekinumab-auub	Ps PsA CD UC	IL-12, −23 & antagonist	10/31/2023
8	Toripalimab-tpzi	NPC	PD-1 & antagonist	10/27/2023
9	Mirikizumab-mrkz	UC	IL-23 & antagonist	10/26/2023
10	Infliximab-dyyb	UC CD	TNF & antagonist	10/20/2023
11	Bimekizumab-bkzx	Psoriasis	IL-17A and F & antagonist	10/17/2023
12	Secukinumab	Psoriasis	IL-17A & antagonist	10/6/2023
13	Tocilizumab-bavi	RA PJIA SJIA	IL-6R & antagonist	9/29/2023
14	Vedolizumab	UC CD	Integrin receptor & antagonist	9/27/2023
15	Ublituximab-xiiy	MS	CD20 & ADCC; CDC	12/28/2022
16	Mosunetuzumab-axgb	FL	CD20; CD3 & cell engager	12/22/2022
17	Adalimumab aacf	RA JIA PsA AS CD UC Ps	TNF & Antagonist	12/13/2022
18	Teplizumab mzwv	Type 1 diabetes	CD3 & Antagonist	11/17/2022
19	Mirvetuximab Soravtansine gynx	EFP	FRα-DM4 & ADC	11/14/2022
20	Tremelimumab actl	uHCC; NSCLC	CTLA-4 &Antagonist	11/10/2022
21	Teclistamab cqyv	MM	BCMA; CD3 & T cell engager	10/25/2022
22	Tremelimumab actl	uHCC	CTLA-4 & Antagonist	10/21/2022
23	Bevacizumab add	mCRC; NSCLC; RG; mRCC; mCC; EFP	VEGF &Antagonist	09/27/2022
24	Spesolimab-sbzo	GPPF	IL-36R & Antagonist	09/01/2022
25	Ranibizumab eqrn	nAMD; RVO; DME; DR; mCNV	VEGF & Antagonist	08/02/2022
26	Risankizumab rzaa	PP; APA; ACD	IL-23 & Antagonist	06/16/2022
27	Bevacizumab maly	mCRC	VEGF & Antagonist	04/13/2022
28	Nivolumab; Relatlimab rmbw	Melanoma	PD-1;LAG-3 & Antagonist	03/18/2022
29	Sutimlimab-jome	CAD	CP & Antagonist	02/04/2022
30	Faricimab-svoa	nAMD; DME	VEGF; Ang-2 7 Antagonist	01/28/2022
31	Tralokinumab-ldrm	Eczema	IL-13	12/27/2021
32	Tezepelumab-ekko	Severe asthma	TSLP	12/17/2021
33	Adalimumab-aqvh	RA	TNF	12/17/2021
34	Ranibizumab	AMD	VEGF	10/22/2021
35	Tisotumab vedotin-tftv	Cervical cancer	Tissue Factor	09/20/2021
36	Ranibizumab-nuna	AMD, RVO, mCNV	VEGF	09/17/2021
37	Dostarlimab-gxly	dMMR EC, Solid tumor	PD-1	08/17/2021
38	Anifro- lumab-fnia	SLE	(I)IFNR	07/30/2021
39	Aducanumab-avwa	Alzheimer’s disease	Amyloid beta	06/07/2021
40	Amivantamab-vmjw	NSCLC	EGFR MET Receptor	05/21/2021
41	Rituximab-arrx	NHL, CLL, GPA, MPA	Anti-CD20, ADCC, CDC	12/17/2020
42	Margetuximab-cmkb	Breast cancer	Anti-HER2, ADCC	12/16/2020
43	Naxitamab-gqgk	Neuroblastoma	Antiglycolipid GD2, CDC, ADCC	11/25/2020
44	Atoltivimab +2	Zaire ebolavirus infection	Zaire ebolavirus glycoprotein	10/14/2020
45	Satralizumab-mwge	NMOSD (AQP4+)	Anti-IL6 receptor	08/14/2020
46	Belantamabmafodotin-blmf	Multiple Myeloma	Anti-BCMA; microtubule inhibitor; ADC	08/05/2020
47	Pertuzumab, trastuzumab, and hyaluronidase-zzxf	Breast cancer (HER2+)	Anti-HER2; increases permeability	06/29/2020
48	Inebilizumab-cdon	NMOSD (AQP4+)	Anti-CD19	06/11/2020
49	Daratumumab and hyaluronidase-fihj	Multiple myeloma	Anti-CD38, ADCC, CDC,	05/01/2020
50	Sacituzumab govitecan-hziy	mTNBC	Anti-Trop-2; SN-38; ADC	04/22/2020

Murine mAbs, chimeric mAbs (where murine variable [V] regions are grafted onto human constant [C regions]), humanized mAbs, which consist of a human Ig scaffold with only the complementarity-determining regions (CDRs) of murine origin, and, most recently, fully human mAbs have all undergone progressive development.¹⁴² The CDRs of a mAb attach to specific targets, resulting in signals or antagonistic behavior. The Fc region of a mAb is made up of the hinge and constant heavy-chain domains (CH2 and CH3), which also perform other functions such as complement fixation and binding to Fc receptors.¹⁴³ The way mAbs are named reflects the type of mAb; for example, the ‘xi’ in rituximab indicates that it is a chimeric mAb.¹⁴⁴

Tolerability

The cardiac tolerability of trastuzumab is relevant as HER2 is overexpressed or amplified in 20%–25% of breast tumors, which correlates with a poor prognosis and reduced overall survival.¹⁴⁵ Trastuzumab is a humanized mAb derived from recombinant DNA that specifically binds to the extracellular region of the HER2 protein.¹⁴⁶ Trastuzumab was later sanctioned for monotherapy in patients with HER2 overexpressing MBC who have received one or more chemotherapy regimens and in conjunction with paclitaxel for those who have not undergone any chemotherapy for metastatic disease.¹⁴⁷ In this study, the response rate was 50% for the trastuzumab plus chemotherapy group, compared with 32% for the chemotherapy-only group, demonstrating enhanced response rates and an increase in survival to 25.1 months for the trastuzumab plus chemotherapy cohort, versus 20.3 months for the chemotherapy cohort alone. Despite notable differences, the cardiac dysfunction induced by trastuzumab exhibits clinically similar characteristics to that caused by anthracycline chemotherapy.¹⁴⁸

Adverse Effects: Infusion-related reactions (IRRs), ranging from minor allergic reactions to anaphylaxis, are frequent adverse events (AEs). Patients who experience anaphylactic symptoms, such as severe respiratory problems or clinically significant hypotension, should think about stopping their medication.¹⁴⁹ Before the antibody–drug conjugate (ADC) infusion, it is advised to take a corticosteroid, antihistamine, and acetaminophen.¹⁵⁰

Gemtuzumab Ozogamicin: The most prevalent adverse effects, occurring in over 30% of cases in monotherapy studies, include pyrexia, nausea, infection, chills, hemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhea, abdominal pain, and neutropenia.¹⁵¹ Neutropenia (34.3%), thrombocytopenia (21.7%), and IRRs (2.5%) were identified as clinically important serious AEs.¹⁵² Hemorrhage and infection were the most prevalent AEs, occurring in over 30% of participants in the combined therapy study.¹⁵³ In the combination therapy research, the most serious AEs included severe infection (41.2%), hemorrhage (9.9%), hepatotoxicity, including Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) (3.8%), and tumor lysis syndrome (1.5%).¹⁵² In the research on combination therapy, thrombocytopenia, VOD, hemorrhage, and infection were the predominant causes for the permanent discontinuation of medication.¹⁵⁴ In monotherapy studies, the primary reasons for discontinuation were infection, hemorrhage, multiorgan failure, and VOD.¹⁵⁵ Patients receiving gemtuzumab ozogamicin as monotherapy, either before to or during Hematopoietic Stem Cell Transplantation (HSCT), together with those exhibiting moderate-to-severe hepatic impairment, demonstrated an elevated risk of developing VOD.¹⁵²

Brentuximab Vedotin: Based on aggregated data from studies utilizing brentuximab vedotin (BV) as a monotherapy, the most prevalent AEs (occurring in 10% of cases) included infections, peripheral sensory neuropathy, nausea, fatigue, diarrhea, pyrexia, upper respiratory tract infections, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, IRRs, pruritus, constipation, dyspnea, weight loss, myalgia, and abdominal pain.¹⁵⁶ Compared to phase II studies, patients who received BV again experienced peripheral motor neuropathy more frequently (28% vs. 9%); however, it was mostly grade 2.¹⁵⁷ Twelve percent of patients experienced serious AEs.¹⁵⁸ Unique significant adverse drug reactions (ADRs) occurred less than 1% of the time. The presence of AEs forced 24% of patients to quit their treatment.¹⁵²

T-DM1: In a cohort of 1871 individuals, the most commonly seen significant ADRs included hemorrhage, pyrexia, dyspnea, musculoskeletal pain, thrombocytopenia, abdominal discomfort, and vomiting. With T-DM1, headache, fatigue, and nausea were the most prevalent ADRs, occurring in 25% of cases.¹⁵⁹ The majority were in first or second grade. Thrombocytopenia, increased transaminases, anemia, neutropenia, fatigue, hypokalemia, musculoskeletal discomfort, and hemorrhage were the most common grade 3 ADRs (>2%) as per the National Cancer Institute’s Common Terminology Criteria for Adverse Events.¹⁶⁰ Severe hepatobiliary disorders have been documented, with clinical research identifying at least two lethal instances of liver failure associated with encephalopathy.¹⁶¹ The predominant indicator of hepatic injury is an elevation in serum transaminases.¹⁶² If blood transaminases go above thrice the upper normal limit and total bilirubin exceeds twice the upper normal limit, T-DM1 should be discontinued permanently.¹⁶³ Among 884 patients, three instances of nodular regenerative hyperplasia of the liver have been observed. Noncirrhotic portal hypertension can arise from nodular regenerative hyperplasia.¹⁶⁴ This toxicity is attributed to a maytansinoid derivative. Upon the identification of nodular regenerative hyperplasia, T-DM1 therapy must be discontinued permanently.¹⁶⁵

Inotuzumab Ozogamicin: The most prevalent AEs occurring in at least 20% of cases included thrombocytopenia (51%), neutropenia (49%), infection (48%), anemia (36%), leukopenia (35%), fatigue (35%), hemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), increased transaminases (26%), abdominal pain (23%), increased gamma-glutamyltransferase (21%), and hyperbilirubinemia (21%).¹⁶⁶ The most prevalent major AEs recorded were infection (23%), febrile neutropenia (11%), hemorrhage (5%), stomach discomfort (3%), pyrexia (3%), VOD/SOS (2%), and tiredness (2%).¹⁶⁷ Among 164 patients, 13% had sinusoidal obstruction syndrome or veno-occlusive disease, including five individuals who did not get HSCT. In addition, 22% of the 77 patients who had HSCT and exhibited veno-occlusive disease/sinusoidal obstruction syndrome were documented. Following HSCT, five instances culminated in mortality.¹⁶⁸ The median interval following HSCT, which was preceded by inotuzumab ozogamicin (INO), was 15 days, and this AE was recorded up to 56 days post the last administration of INO as the sole treatment. Factors such as being under five years of age, undergoing a conditioning regimen with two alkylating agents, and having elevated blood bilirubin levels before HSCT were additional risk factors.¹⁶⁹

Combination therapy with mAbs in BC

The use of mAbs in oncology has become more important and highly beneficial in the BC treatment. The combination therapy of mAbs is highly suitable because of limited overlapping toxicity and lack of pharmacokinetic interactions. By the combination therapy of mAbs, different pathways can be targeted and, thus, exhibits leading additive or synergistic effects.⁷¹

Combination of TRA-8 with adriamycin or paclitaxel for TRA-8 sensitive BC

The anti-DR5 mAb Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand 8 (TRA-8) binds to the human death receptor DR5 and has efficacy against BC tumors.¹⁷⁰ In TRA-8 sensitive BC cell lines, the combination of TRA-8 with chemotherapeutic agents such as adriamycin (an anthracycline) or paclitaxel (a taxane) yields a superior antitumor impact compared with either agent administered independently.¹⁷¹ In certain cell lines, the therapeutic effect will be additive, whereas in others, it will be synergistic.¹⁷²

Trastuzumab in combination with other antitumor medications for HER2-positive BC

Trastuzumab, a mAb to herceptin, specifically targets the HER2 gene and promotes cell death via ADCC. This medicine exhibits a synergistic impact when administered in conjunction with other antitumor agents such as nimotuzumab, carboplatin, 4-hydroxycyclophosphamide, docetaxel, and vinorelbine.¹⁷³ The combination of trastuzumab and chemotherapy for one year will enhance the patient’s survival outlook.¹⁷⁴ In the treatment of HER2-positive MBC, the combination of trastuzumab and docetaxel demonstrated superior efficacy compared with docetaxel monotherapy.¹⁷⁵ In MBC, the combination of trastuzumab and chemotherapy exhibits a superior objective response rate and a reduced rate of disease progression.¹⁷⁶ Adverse consequences of trastuzumab-based therapy encompass congestive heart failure and a decrease in left ventricular ejection fraction.¹⁷⁷

Pertuzumab–Trastuzumab–Docetaxel combination for HER2+ BC

The amalgamation of pertuzumab, trastuzumab, and docetaxel is sanctioned for the management of HER2-positive breast carcinoma.¹⁷⁸ HER+ tumors exhibited significantly elevated rates of pathological complete response (pCR) and invasive disease-free survival compared with HER- tumors. The adverse effects of this medication are febrile neutropenia and diarrhea.¹⁷⁹

Rational combination therapy

The clinical benefit of antibodies is maximized when they are rationally combined with other anticancer medications and substances that target the immunosuppressive TME.¹⁸⁰

Combination of immune checkpoint blockade (Pembrolizumab) with Trastuzumab for HER2+ BC

Immune checkpoint blockade (ICB) antibody inhibitors have a significant impact on the treatment of BC. Combining trastuzumab with ICB helps overcome the resistance to trastuzumab monotherapy.¹⁸¹ Trastuzumab and pembrolizumab, the ICB, exhibit a synergistic effect that results in excellent results in HER2+.¹⁸²

Combination of trastuzumab with lapatinib for HER2+ BC

Lapatinib is a kinase inhibitor that inhibits the activity of HER1 and HER2 tyrosine kinases, as well as cell proliferation.¹⁸³ Lapatinib and trastuzumab together appear to promote immune-mediated trastuzumab-dependent cytotoxicity.¹⁸⁴

AC regimen for HER2+ and node+ BC treatment

Node-positive, HER2+ BC patients are being randomly assigned under the National Surgical Adjuvant Breast and Bowel Project-B31 protocol to either four cycles of AC (adriamycin and cyclophosphamide) followed by four cycles of paclitaxel or the same regimen plus trastuzumab in combination with paclitaxel. Trastuzumab is also given either concurrently with paclitaxel therapy or following the conclusion of AC and paclitaxel therapy.¹⁸⁵

Combination of trastuzumab with cyclin-dependent kinase inhibitor (flavopiridol) for HER2+ BC

Trastuzumab and the cyclin dependent kinase inhibitor flavopiridol work synergistically to prevent the survival of BC cells that overexpress the HER2 gene.¹⁸⁶

Combination of bevacizumab with vinorelbine for refractory MBC

In phase II clinical studies, vinorelbine and bevacizumab were used to treat patients with resistant MBC.¹⁸⁷

Combination of bevacizumab with capecitabine

In the bevacizumab phase III clinical study for BC, patients with metastatic disease who had previously received treatment were randomly assigned to receive either capecitabine alone or capecitabine + bevacizumab as part of their treatment.¹⁸⁸ The major end point of the study, the ORR, improved significantly when bevacizumab was added to capecitabine (19.8% versus 9.1%), although there was no difference in progression-free survival.¹⁸⁹

Resistance to mAbs

Although mAb therapy has proven effective in cancer treatment, clinical resistance to these agents continues to pose a substantial challenge.¹³⁴ The majority of individuals exhibit refractory disease within one year, with just a minor proportion of patients responding to treatment. Therapeutic resistance may be categorized as innate (primary) or acquired (secondary), with diverse mechanisms contingent upon the context.¹⁹⁰

Innate resistance

Innate resistance primarily arises from alterations that exist in tumor cells before treatment.¹⁹¹

Acquired resistance

Acquired resistance results from immune selection pressure and immunoediting of the tumor during treatment.¹⁹² Preclinical models and clinical trials utilizing mAb treatment have revealed the induction of alternative growth signaling pathways, epithelial–mesenchymal transition (EMT), inadequate effector cell responses, mutations in the antibody target, and various other resistance mechanisms.¹⁹³ The efficacy of mAb therapy is limited by the expression of target molecules on tumor cells that the antibodies may attach to.⁷³ Although mutations in the CD20 gene can confer irreversible resistance to rituximab in lymphoma patients, such alterations were rarely observed at the onset of treatment.¹⁹⁴ HER2 expression remained unchanged in BC patients treated with trastuzumab, despite conflicting results from in vitro studies.¹⁹⁵ It is shown that Signal Transducer and Activator of Transcription 1 (STAT1)-mediated pathways can lead to the downregulation of HER2 upon exposure to IFN-γ.¹⁹⁶ Moreover, trastuzumab-induced ADCC triggers the release of IFN from NK cells, subsequently leading to the downregulation of HER2 expression in a STAT1-dependent manner, so resulting in concomitant resistance to trastuzumab.¹⁹⁷ PD-L1 is recognized to be increased on the surface of tumor cells due to the activation of IFN-induced STAT1 signaling, which confers resistance to NK cell-mediated ADCC.¹⁹⁸ Primary resistance to trastuzumab in BC is linked to genetic features associated with EMT.¹⁹⁹ A subset of patients undergoing extended trastuzumab therapy for HER2 positive/PTEN negative breast tumors exhibited EMT, which facilitated acquired resistance.²⁰⁰ Mutations in the antibody target and associated downstream signaling molecules may induce acquired resistance to mAb therapy by activating alternative growth or survival signaling pathways.²⁰¹

The absence of MHC Class I Polypeptide-Related Sequence A (MICA) and other ligands for the Natural Killer Group 2 Member A (NKG2A)-Human Leukocyte Antigen (HLA)-E axis in cancer cells, which stimulate NK cells, can inhibit NK cells from initiating ADCC.²⁰² The downregulation of many cell surface proteins associated with the immunological synapse in reaction to cetuximab and trastuzumab is a recently identified distinct mechanism of ADCC resistance.²⁰³ Clinical resistance often entails less cytotoxic immune effector cell responses, with antibody-dependent cell-mediated cytotoxicity (ADCC) regarded as the principal therapeutic mechanism of mAb treatment.¹³² Capuano et al. elucidated a distinctive mechanism of immunological weariness, demonstrating that CD16 ligation resulted in NK cells, continuously exposed to rituximab, losing their cytotoxic capabilities.²⁰⁴ Checkpoints on NK cells can regulate ADCC as well. The blockade of these receptors enhanced trastuzumab-based responses in BC patients.²⁰⁵ Poliovirus receptor-like receptors, including TIGIT, are recognized for their role in trastuzumab-mediated ADCC of cancer cells by NK cells.¹⁹⁷

The synthesis of several proteins essential for the immunological synapse is also required for NK cell-mediated ADCC. While this may seem less critical for trastuzumab-mediated ADCC, ADCC is somewhat reliant on recognition via Intercellular Adhesion Molecule 1 (ICAM-1) and CD18.²⁰⁶

Future directions for mAb therapy

The uses and methodologies of mAbs are continually advancing to enhance therapy outcomes for BC patients. These innovative therapeutic methods have markedly enhanced survival rates.²⁰⁷ The enhancements in survival rates for patients with HER2-positive BC have been facilitated by the advent of HER2-targeted therapies, such as trastuzumab, pertuzumab, and more recently, tucatinib and trastuzumab deruxtecan.²⁰⁸ Currently, early BC patients undergoing chemotherapy and dual antibody therapy exhibit survival rates of 90%.²⁰⁹

Notwithstanding this accomplishment, the emergence of mAb resistance has been increasing, mostly contributing to disease progression and suboptimal therapeutic outcomes.²¹⁰ Consequently, rigorous research is underway in the preclinical, translational, and clinical domains to develop innovative and more efficacious therapies for HER2, a very sensitive target.²¹¹

ADCs

Targeting HER2 has advanced thanks to the increased use of ADCs, which can now have their linkers, payloads, or antibody scaffolds modified for maximum effectiveness.²¹² Several HER2-targeted ADCs of the next generation are presently being tested in clinical studies.²¹³ To increase the effectiveness and tolerability of these new drugs, several payloads and linker technologies have been used in their design (Fig. 1).²¹⁴

A166

Trastuzumab is conjugated with the auristatin derivative duostatin-5 as the payload of A166, an ADC.²¹² A phase I trial involving 27 evaluable patients yielded initial efficacy data in 2020, demonstrating a disease control rate of 59% and partial responses in 7 patients (26%) at dose levels of 3.6 mg/kg and 4.8 mg/kg.²¹³ Current results are pending for this ongoing experiment (NCT03602079).²¹⁵

Trastuzumab duocarmazine

The HER2 ADC SYD985, often referred to as vic-trastuzumab duocarmazine, has a trastuzumab backbone connected by a cleavable linker to a duocarmycin payload, a potent DNA alkylating agent, which includes its inactive prodrug form, seco-duocarmycin.²¹³ Given that the payload in this context is membrane-permeable, it may also infiltrate adjacent cells, regardless of HER2 expression.²¹⁶ The HER2-positive and “HER2-low” breast tumors, characterized as HER2 1+ or 2+/ Fluorescence In Situ Hybridization (FISH) nonamplified, demonstrated indications of anticancer efficacy in the phase 1 study of this ADC.²¹³

Bispecific antibodies

An alternative approach is the development of bispecific antibodies that enhance efficacy by targeting two separate HER2 epitopes.²¹⁷

Therapeutic approaches for TNBC

TNBC has gained from immunotherapy, and initiatives to stimulate the immune response in HER2-positive cases are currently in progress.²¹⁸ Immunotherapy can be approached through several methods, including checkpoint inhibitors, cellular treatment, vaccines, and the conjugation of effector T cells with HER2 antibodies, among others.²¹⁹

Combination of ADC with antitumoral drugs

A novel class of drugs has been developed based on the complementary actions of HER2 inhibition and chemotherapy.²²⁰ ADCs are pharmacological entities that combine the anticancer effects of both of these methods. It has FDA approval.²²¹

Combination of trastuzumab with lapatinib

The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial is the inaugural study to report in 2014 on the efficacy of dual anti-HER2 therapy with trastuzumab and lapatinib (either sequentially or concurrently) versus trastuzumab monotherapy.²²² Patients with HER2-positive primary BC participating in the APHINITY trial are receiving pertuzumab alongside trastuzumab and standard nonanthracycline chemotherapy.²²³ The KATHERINE study examines the effects of postoperative T-DM1 compared with trastuzumab in patients with HER2-positive disease who exhibit less than a pCR following preoperative therapy with a trastuzumab-based regimen.²²⁴

Combination of trastuzumab with ZD1839

A phase II trial by the Eastern Cooperative Oncology Group is administering a combination of ZD1839 and trastuzumab to patients with MBC exhibiting HER-2 overexpression.²²⁵ By inhibiting HER-2 transactivation, EGFR inhibition may enhance trastuzumab response rates. In trastuzumab-resistant tumors, where compensatory signaling by EGFR may hinder the response to trastuzumab, such a combination may also be considered.²²⁶

Obesity-associated BC

Humanized monoclonal antibody–blocking fatty acid binding protein 4 (FABP4) activity (PMID: 39054536): The risk of BC is increased by obesity, although the underlying molecular pathways are unclear. Adipose FABP (A-FABP, or FABP4) may provide a new target for the therapy of BC by establishing a connection between the risk of BC and obesity-induced dysregulated lipid metabolism.²²⁷ A study used screened hybridoma clones with specific binding to FABP4, and immunized FABP4 knockout mice with recombinant human FABP4 revealed the creation of humanized mAbs that inhibit FABP4 activity in mice models to treat BC. One clone, 12G2, was chosen for additional analysis because it dramatically decreased the levels of FABP4 in the blood and stopped the growth of breast tumors. Sixteen humanized 12G2 mAb variants were created by grafting its CDRs to specific human germline sequences following confirmation of the therapeutic efficacy of the chimeric 12G2 mAb, which consists of mouse variable regions and human IgG1 constant regions. The humanized V9 mAb consistently inhibited the growth and spread of breast tumors by altering the mitochondrial metabolism of tumor cells.²²⁸

Trastuzumab: Obese women had a lower DFS (HR 1.31, 95% Confidence Interval (CI) 1.07–1.59) than women of normal weight in a secondary analysis of the N9831 trial, which compared chemotherapy with or without trastuzumab in nearly 3400 women with HER2-positive, early-stage BC.²²⁹ Although the trial was not sufficiently powered to detect a statistically significant difference based on the treatment received, this investigation indicates that IV adjuvant trastuzumab may improve clinical outcomes independent of Body Mass Index (BMI).²³⁰

Sacituzumab govitecan-hziy: It is authorized for use in patients with Hazard Ratio (HR)-positive, HER2-negative, triple-negative, or resistant MBC.²³¹ Pharmacokinetic studies that demonstrate a correlation between body weight and the amount of drug distribution and clearance have led to weight-based dosing.²³² To the best of our knowledge, no research has evaluated how BMI affects sacituzumab govitecan-hziy’s toxicities and clinical results in BC patients.²³³

Pembrolizumab: Subsequent pharmacokinetic studies demonstrate that a fixed-dosing method results in no clinically meaningful differences in efficacy and safety, confirming the current FDA recommendation of a fixed dose, even though early clinical trials of pembrolizumab used a weight-based dosing technique.²³⁴ There is a dearth of information on how obesity affects immunotherapy clinical results.²³⁵ In addition, this work raises the possibility that immunotherapy may produce a potent antitumor immune response in obese BC patients, which calls for additional validation through carefully planned clinical studies.²³⁶

Numerous scientific studies, however, have shown that to increase the overall survival rate and quality of life of BC survivors who are obese, we must use various complementing strategies.²³⁷ Therefore, in addition to the standard therapeutic management, it is imperative to use complementary nutritional interventions as adjuvant therapy to reduce obesity and its associated consequences with regard to the prevalence of BC.²³⁸

Conclusion

mAbs are multitaskers that suppress checkpoints, to put it briefly. They were heavily utilized in research applications. These mAbs treat tumors and lessen the harmful side effects of chemotherapy.²³⁹ They also treat autoimmune, cardiovascular, cancer, and inflammatory illnesses. They respond to immune system-targeted, minimally harmful treatment. They might have widespread negative impacts.²⁴⁰ Cardiovascular patients can tolerate mAbs for BC. For the greatest clinical benefit, these mAbs are combined with other anticancer medications.¹¹

Footnotes

Acknowledgments

The authors are thankful to the School of Pharmaceutical Education and Research, Jamia Hamdard, and St. Pauls College of Pharmacy, Telangana, for encouragement and support.

Authors’ Contributions

R.S., V.M., S.B., and A.R. contributed to study conception, data collection, and article preparation. B.M., V.S.H., R.K., B.S., and S.T. designed, reviewed the results, and approved the final version of the article.

Ethical Approval

Not required.

Author Disclosure Statement

The authors declare no conflicts of interest.

Funding Information

Authors received no funding for this research.

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