**9. Effector mechanism of antibodies**

*Advances in Precision Medicine Oncology*

**8. Targets for resistant tumors**

It is a receptor present on the cell membrane which is responsible for obtaining iron inside the cell. Iron binds to transferrin, and this complex binds to the receptor, which is then internalized [36]. Iron is necessary for many functions, such as DNA synthesis. This receptor can be targeted even if the tumor is Multi-drug resistant. Targeting this receptor has shown excellent results in resistant tumors such as increased formulation internalization, reduced drug required, higher cell death, and enhanced cytotoxicity [37]. This receptor's drawback is its presence at non-

Human epidermal growth factor receptor-2 (HER-2) is a receptor spanning across the cell membrane with having a protein kinase internal subunit [38]. It is excessively expressed in gastric, lung, breast, and ovarian cancers. Overexpression of this receptor makes it challenging to forecast carcinoma. But, commercial products such as Herceptin have shown a promise targeting this receptor [39]. Targeting the HER-2 may help in cases of tumors showing resistance. This type of targeting has also demonstrated reduced cancer cell viability, enhanced cytotoxicity in resistant tumors, and increased uptake in the studies. A significant drawback is the absence of any natural ligand for the HER-2 receptor, which makes targeting

Cancer cells are derived from normal body cells; hence they have a similar receptor constitution on the cell surface. Due to this lack of specialized markers, chemotherapeutic agents cannot differentiate between normal and cancer cells. Hence, they show toxicity. Keeping a low dose may result in resistance [40]. Therefore to achieve a specific targeting, antibodies specific for antigens presented by cancer

IgG is the majorly used antibody for targeting cancer [41]. Antibodies have 'Y' shaped structures where two arms have the sites for antigen binding. Monoclonal antibodies which are derived from a single clone of cells themselves or only the targeting fragments, can be used for cancer therapy. These agents bind the antigen and cause cell death by antibody-dependent toxicity, complement activation, or blocking signal transduction inside the cell. The antibody has a high affinity for its specific antigen and has excellent binding strength due to the presence of two binding sites. Entire antibodies may cause activation of the immune system inside the body. And due to their long half-lives, detection also becomes an issue. Using antibodies from species other than humans may cause severe allergic reactions. Hence to combat this situation, researchers have developed various molecules based on antibodies. Antibodies have been developed where binding sites from mouse have been attached to human antibody (chimeric antibody), humanized or human antibodies have also been developed. Researchers have separated the Fc fragments

responsible for binding and have used them for targeting.

malignant sites such as endocrine glands may cause a loss in efficacy.

**8.1 Transferrin receptor**

**8.2 HER2**

difficult [39].

cells can be targeted.

**8.4 Engineering of antibodies**

**8.3 Antibodies for targeting cancer**

**82**

Antibodies usually target antigens that are unique to cancer cells or which are excessively expressed on the cell surface. The majority of antibodies induce cancer cell death by binding to their target receptor, either blocking the receptor or changing the receptor's activation requirements [42]. They disturb signaling pathways responsible for cell growth and survival; hence, they end up killing the cells [43]. For example, Cetuximab is an antibody directed against EGFR. Epidermal growth factor upon binding to EFGR causes tumor growth, proliferation, and migration. EFGR is seen in many cancers. Cetuximab binds to EGFR and blocks the receptor hence preventing ligand binding and subsequent receptor dimerization. This process leads to apoptosis. Human epidermal growth factor receptor 2 is a member of the tyrosine kinase family. It is overexpressed in breast and ovarian cancers. The unique feature of this receptor is the absence of any known natural ligand. Instead, it forms dimers with other growth factor receptors and exerts its effects. Hence antibodies that are made to target this receptor prevent its dimerization with any other receptor and prevent survival.

Indirect action of antibodies involves host immune system participation and causes cytotoxicity by activation of complement system, antibody-dependent phagocytosis, and antibody-dependent cytotoxicity. Most antibodies are able to activate the complement system, which targets and destroys the cancer cell. Ofatumumab, an anti-CD20 antibody, intensifies the process of cytotoxicity through complement activation. Antibody-dependent phagocytosis occurs after a cancer cell opsonized by mAb attaches to a macrophage FcyRI glycoprotein. Then macrophage consumes such a marked cell [44].
