In this article, we will give an introduction to monoclonal antibody applications in cancer, the six mechanisms of treatment, monoclonal antibiotic nomenclature, pharmacologic options, and the subcutaneous
Monoclonal antibodies in cancer
As with any monoclonal antibodies, the agents used in cancer are also specific. Some are cancer-specific, but this is not always true. Unlike tyrosine kinase, monoclonal antibodies’ binding site is always extracellular. Also unlike tyrosine kinase, most of these agents are either IV or SQ.
Dosing can be based on BSA, mg/kg, or flat dosing.
Similarly to tyrosine kinase inhibitors, their goal is to block oncogenic processes, not always to kill cancer cells.
Most monoclonal are derived from cultures, mostly mice, humans, or a combination of the two. Most are IgG with standard IgG constant region (Fc). Each has a variable Fab that was modified to target specific targets.
Monoclonal Antibody Nomenclature (Historical and New)
Historical System (prefix + target infix + source infix + mab)
- Prefix can be anything
- Target infix is what the monoclonal is targeting
- os | bone
- vi | viral
- ba | bacterial
- li | immune
- ci | cardiovascular
- ki | interleukin
- tu | tumor
- toxa | toxin
- fu | fungal
- Source infix is how the monoclonal was derived
- u | human
- o | mouse
- a | rat
- e | hamster
- i | primate
- xi | chimeric
- zu | humanized
- axo | rat/mouse
Source infix is helpful in predicting the risk of infusion reaction
New System (prefix + target infix + mab + random 4 letters)
Many of the target infixes are the same, except for tumor: From Tu to Ta.
Six Mechanisms of Treatment
There are six mechanisms: Receptor complex blockage, ADCC, CDC, ADCP, Targeted delivery of cytotoxic molecules, and Targeted delivery of radiation
Receptor Complex Blockage (RCB) – “Blocking directly”
In this mechanism, monoclonal can bind directly to the receptor or ligand to block the effects. An example is bevacizumab (beva – prefix, ci – cardiovascular, zu – humanized, and mab)
Antibody-Dependent Cellular Cytotoxicity (ADCC) – “T-cell and NK recruits”
A lot of monoclonal go through this mechanism. These agents act as normal antibodies that have their Fab regions bind to the cancer cell with the Fc regions sticking out to recruit killer T-cell and NK-1 cells to perform the cell lysing.
Complement-Dependent Cytotoxicity (CDC) – “complement protein”
These agents act similarly to the ADCC agents where Fab regions bind to the cancer cell, and the Fc regions stick out. In this case, the Fc region recruits complement proteins. Upon binding, the complement proteins activate the complement cascade, make the cylindrical complex that pierces the cancer cell membrane, and kill the cell.
It is important to note that many agents that utilized ADCC, may also rely on CDC to a certain extent.
Antibody-Dependent Cellular Phagocytosis (ADCP) – “phagocytes”
These agents’ Fc regions recruit phagocytes. Upon binding, the phagocytes envelop and consume the target, which can be either a cell or a protein.
This is not as common as other mechanisms.
Delivery of Cytotoxic Molecules – “cytotoxic”
The monoclonals are crosslinked to cytotoxic molecules. This crosslink must be stable enough that it only dissolves when the antibody gets internalized and eaten up by the cancer cell’s lysosome. The crosslink must be susceptible to lysosomal enzymes and dissolved upon exposure, releasing the attached cytotoxic agent to cause cell lysis.
Delivery of Radioactivity – “radioactive”
The mechanism of this is similar to cytotoxic agents, but the antibodies are crosslinked to radio-isotope instead. When the crosslink releases the radioactive isotope, it emits short-range emissions to kill the cell.
It is important that the emission is only short-range so that the patients can have a normal life. While these patients have some limitations, for the most part, they can proceed normally.
Monoclonal Antibody Agents
There are also six main classes of agents: EGFR inhibitors, Her2/Neu inhibitors, VEGF inhibitors, CD inhibitors, and GD2 inhibitors.
Epithelial Growth Factor Receptor (EGFR) inhibitors – “Ineffective in RAS mutation”
Agents:
- Cetuximab (RCB – ligand and ADCC) – Ce (prefix) + tu (tumor) + xi (chimeric) + mab
- Panitumumab (RCB – ligand and internalization) – Pani (prefix) + tu (tumor) + u (human) + mab
- Necitumumab (RCB – ligand, ADCC, internalization) – Neci (prefix) + tu (tumor) + u (human) + mab
- Amivantamab (RCB – receptor + ligand and ADCC) – Amivan (prefix) + ta (tumor) + mab
Remember that monoclonal antibodies (MABs) bind intracellularly. Because of this, we have to worry about downstream effect mutations, such as RAS mutation. If patients have RAS proto-oncogenes, these agents are useless.
One big difference between tyrosine kinase inhibitors (TKIs) and EGFR MABs is that MABs target all EGFR while TKIs only target mutated EGFR.
Class ADRs: Similar to TKI (acneiform, photosensitivity) plus magnesium wasting (must be monitored and supplement as needed)
Her2/Neu Inhibitors – “Premedicate with APAP”
Agents (ADCC):
- Trantuzumab – Tran (prefix) + tu (tumor) + zu (humanized) + mab
- Pertuzumab – Per (prefix) + tu (tumor) + zu (humanized) + mab
- Margetuximab – Marge (prefix) + tu (tumor) + xi (chimeric) + mab
There are also trastuzumab emtansine and fam-transtuzumab deruxtecan-nxki (Enhertu)
Class ADRs: cardiotoxicity (reversible – ECHO baseline and periodically), embryofetal toxicity, and infusion reactions – premedicate with APAP.
Vascular Endothelial Growth Factor (VEGF) Inhibitors – “angiogenesis”
Agents:
- Bevacizumab (RCB – ligand (growth factor)) – Beva (prefix) + ci (cardiovascular) + zu (humanized) + mab
- Ramucirumab (RCB – ligand and receptor) – Ramu (prefix) + ci (cardiovascular) + u (human) + mab
Just like their TKI counterpart, they inhibit angiogenesis. Because these agents bind to the ligands themselves, we do not have to worry about the downstream event.
Class ADRs: Because we are messing around with the cardiovascular system, we expect to see hypertension, thrombosis, bleeding, and impaired wound healing. It is recommended that blood pressure and urinalysis for kidney damage are monitored.
Cluster of Differentiation (CD) Inhibitors – ” CD30, CD20, and CD38″
These agents help control the up-regulated B-cells in lymphomas, chronic lymphocytic leukemia, and multiple myeloma.
Agents target CD30:
- Brentuximab vedotin – Bren (prefix) + tu (tumor) + xi (chimeric) + mab
Brentuximab is used to treat Hodgkins Lymphoma. It is complexed with vedotin (MMAE), which is a microtubule-disrupting agent. Upon binding, it releases MMAE into the CD30 B-cells.
Brentuximab ADRs: severe neurologic toxicities (peripheral), infusion reactions, and tumor lysis
Agents target CD38 (ADCC, CDC, ADCP):
- Daratumumab – Dara (prefix) + tu (tumor) + u (human) +mab
- Isatuximab – Isa (prefix) + tu (tumor) + xi (chimeric) + mab
These agents are used for multiple myeloma. They have severe infusion reactions, and patients must be pre and post-medicated for this. The subcutaneous formulation can greatly reduce this reaction.
Blood type testing should be done prior to CD38 agents therapy due to the interferance with cross-matching for RBC screening.
Agents target CD20 (ADCC and CDC):
- Rituximab (has non-oncology indication as well) – Ri (prefix) + tu (tumor) + xi (chimeric) + mab
- Ofatumumab (CLL) – Ofa (prefix) + tu (tumor) + u (human) + mab
- Obinutuzumab (CLL) – Obinu (prefix) + tu (tumor) + zu (humanized) + mab
These agents are typically used for CLL. There are some caveats with these agents. First, they can cause both infusion reactions and tumor lysis syndrome. This makes it difficult to distinguish between the two ADRs. It is recommended that the treatment start slowly for the first couple of doses, then the patients can go to rapid infusion. Second, they can increase the rate of hepatitis B reactivation. Patients should be checked for hepatitis B prior to the treatment.
Disialoganglioside (GD2) Inhibitors – “Morphine infusion”
Agents (ADCC and CDC):
- Dinutuximab – Dinu (prefix) + tu (tumor) + xi (chimeric) + mab
- Naxitamab-gpgk – Naxi (prefix) + ta (tumor) + mab
These agents are mainly used in pediatric neuroblastoma. Because they attack nerve cells, this leads to severe neuropathic pain. Patients should be infused with morphine during the infusion and for 2 hours post-infusion.
Subcutaneous Monoclonals
Many MABs can be given subcutaneously by combining them with hyaluronidase. This compound breaks down hyaline (connective tissues), allowing for a higher dose and a higher quantity per injection.
Normally, subcutaneous injections are limited to 2 mL per dose, but this allows up to 15 mL.