Monoclonal Antibody

Alternatively myeloma cells can be selected to be deficient in enzyme thymidine kinase (TK) by growth in bromodeoxyuridine.

Monoclonal antibody against VEGF REF: Goodman Gillman’s 11′^h ed p. 915 

See APPENDIX-34 for “FDA approved monoclonal antibodies”

BEVACIZUMAB: Bevacizumab (AVASTIN) targets the vascular-endothelial growth factor (VEGF) and inhibits its interaction with the VEGFR1 and VEGFR2 receptors. VEGF is an angiogenic growth factor that regulates vascular proliferation and permeability and inhibits apoptosis of new blood vessels. Use: Bevacizumab is FDA approved for metastatic colorectal cancer in combination with 5-FU. Side effects: Hypertension, pulmonary hemorrhage, gastrointestinal perforation, proteinuria, congestive heart failure

Uses of Herceptin (trastuzumab)

• Currently transtuzumab is approved for HER2/ neu overexpressing metastatic breast cancer in combination with paclitaxel as initial treatment or as monotherapy following chemotherapy.

Bevacuzimab

Trastuzumab (HERCEPTIN) is a humanized monoclonal antibody that binds to the external domain of HER2/neu (ErbB2).

Trastuzumab was the first monoclonal antibody to be approved for the treatment of a solid tumor.

Thirty percent of breast cancers overexpress this receptor due to gene amplification on chromosome 17.

By blocking the complement cascade downstream of C5, eculizumab abolishes complement-dependent intravascular hemolysis in all PNH patients, and significantly improves their quality of life.

A major advance in the management of PNH has been the development of a humanized monoclonal antibody, eculizumab, directed against the complement component C5.

By blocking the complement cascade downstream of C5, eculizumab abrogates complement-dependent intravascular hemolysis in all PNH patients.

Patient in the question is showing features of mantle cell lymphoma.

Mantle cell lymphoma is a subtype of non Hodgkins lymphoma.

Patients often presents with lymphadenopathy at several sites along with fever, night sweats or weight loss. On examination hepatomegaly and spleenomegaly is evident.

Investigations: Translocation of chromosome t(11:14) result in over expression of cyclin D1. Biopsy of lymph node mostly shows a diffuse enlargement of lymph node, rarely a mantle zone pattern. The flow cytometery shows CD 19 +, CD5 +, CD23 -ve monoclonal B-cells with bright kappa positivity.

A i.e. Produced by hybridoma technology;  B i.e. Used for blood grouping; C i.e Requires in small quantity

Ans. is ‘a’ i.e., Monoclonal antibody against VEGF

Bevacizumab is monoclonal anti-VGEF antibody. It is used in colon, lung and breast cancers.

Ans. is ‘c’ i.e., Chimeric monoclonal antibodies

Ans. is ‘b’ i.e., It is monoclonal antibody produced by injecting HER-2 antigen

o Herceptin is a humanized antibody and is used in breast cancers which are HER2 positive.

Ans. is ‘a’ i.e., Trastuzumab

o Trastuzumab, a HER2/neu receptor blocker and is used in breast carcinoma causes dilated cardiomyopathy.

Ans. is ‘b i.e., Osteoporosis

Donesumab

o Osteoclast is a cell responsible for bone resorption.

o Osteoclasts express RANK receptors on its surface (RANK —> receptor activator for nuclear factor).

o When RANK receptor combine with their ligands (RANKL) osteoclastogenesis is initiated and bone resorption occurs.

o Donesumab is a monoclonal antibody against RANK ligand. o It prevents the activation of the osteoclasts by these ligand.

Note :

o Osteoporosis is a disease characterized by decrease in the bone mass.

o In osteoporosis there is increase in the osteoclast activity and there is increased expression of RANK and RANKL.

Ans is ‘c’ i.e. Responds well to monoclonal antibodies 

The HER2 receptor (previously called HER2/neu, or ERBB-2 receptor) belongs to the epidermal growth factor receptor (EGFR) family of receptors, which are critical in the activation of subcellular signal transduction pathways controlling epithelial cell growth and differentiation and possibly angiogenesis.

Amplification of HER2 or overexpression of its protein product is observed in 18 to 20 percent of human breast cancers.

HER2 overexpression is also noted in other tumors such as esophagogastric tumors, lung, ovary & head and neck squamous cell ca. (In all of these sites, HER2 overexpression has been identified as a negative prognostic factor.)

Following points are to be noted about HER2 overexpression in breast Ca:

Prognostic value of HER2 — HER2 overexpression is a poor prognostic marker. HER2 overexpression is associated with high rates of disease recurrence and death in the absence of adjuvant systemic therapy.

Predictive value of HER2 — HER2 status predicts response to specific therapies:

• Patients with high levels of HER2 expression benefit from treatment with agents that target HER2, such as trastuzumab (a monoclonal antibody) and lapatinib.
• HER2 status appears to predict resistance or sensitivity to different types of chemotherapeutic agents, including anthracyclines and taxanes.

Women whose tumors overexpress HER2 appear to derive greater benefit from anthracycline-based adjuvant therapy than from adjuvant therapy that is alkylating agent-based, such as CMF (cycl ophosphami de, methotrexate, fluorouracil).

Relationship between HER2 overexpression and taxanes is still under study with various studies giving conflicting reports.

HER-2 positivity is associated with resistance to endocrine therapies.

Answer is B (Plasmacytoma)

Presence of a solitary lytic lesion of the bone with monoclonal plasma cells suggests a diagnosis of Solitary Plasmacytoma of Bone. A small M spike may be identified in some patients but Bone Marrow biopsy taken some distance away from the primary site is typically not involved typically showing < 10 percent plasma cells

Solitary Bone Plasmacytoma

The diagnosis of SBP requires histologic evidence of a monoclonal plasma cell infiltrate in a single bone lesion, absence of other bone lesion on skeletal survey, and lack of marrow plasmacytosis elsewhere. Furthermore, there should be no evidence of anemia, hypercalcemia, or renal dysfunction that could be attributed to the plasma cell proliferative disorder spike may be identified in some patients hut Bone Marrow biopsy taken some distance away from the primary site is not involved typically showing < 10 percent plasma cells.

Diagnostic criteria for Solitary Plasmacytoma of bone and Extramedullary Plasmacytoma

• Solitary Osseous lesion or Extramedullary lesion due to clonal plasma cell proliferation
• Normal marrow with no evidence of clonal plasma cells or aneuploidy by flow-cytometry.
• Normal skeletal survey with proximal humeri and femora and a
• Normal magnetic resonance image of the axial skeleton (for Solitary Plasmacytoma of Bone); or a
• Normal regional computed tomographic scan (for Extramedullary Plasmacytoma).
• Absent or low serum or urinary concentration of monoclonal protein.
• No anemia, hypercalcemia, or renal insufficiency attributable A myeloma.

Answer is D (Strongly Positive Rheumatoid factor):

Type I Cryoglobulinemia (simple cryoglobulinemia) is typically associated with Monoclonal IgM paraprotenemia producing a Hyperviscosity type syndrome. Type I Cryoglobulins rarely have Rheumatoid Factor Activity and do not activate complement in vitro (hence complement levels are usually normal).

`Monoclonal Cryoglobulins (Type I) rarely exhibit Rheumatoid Factor activity and do not interfere with complement mediated function in vitro’

— ‘Cryoglobulins and Cryoglobulinemia’ from Clinical Reviews in Allergy and Immunology: Vol 16, Number 3 (1998) page 249-264

`Type I Cryoglobulins do not activate the complement cascade and are therefore associated with normal complement levels’

Mixed Cryoglobulinemias (Type II/Type III) are associated with Strongly Positive Rheumatoid Factors and  Reduced Complement levels.

Hypocomplementemia occurs in 90% of patients with mixed cryoglobulinemias.

Rheumatoid factor is positive in 80-100% ofpatients with mixed cryoglobulinemia

 Cryoglobulinemia

• Cryoglobulins are immunoglobulins that precipitate as serum is cooled below core body temperature (below 37° C) and re-dissolve on re-warming.
• Cryoglobulinemia is characterized by the presence of cryoglobulins in the serum.
• Cryoglobulinemia is most commonly classified into three types in accordance with the Brouet Classification based on the components of the cryoprecipitate.
• Type I (Simple Cryoglobulinemia) and Type II, Type III (Mixed cryoglobulinemia)

Ans. B: Monoclonal light chains

A Bence Jones protein is a monoclonal globulin protein found in the blood or urine, with a molecular weight of 22-24 kDa. The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplastic plasma cells. They can be kappa (most of the time) or lambda.

The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins.

They are found in urine due to the kidneys’ decreased filtration capabilities due to renal failure, often induced by hypercalcemia from the calcium released as the bones are destroyed.

The light chains can be detected by heating or electrophoresis of concentrated urine. Light chains precipitate when heated to 50 – 60 degrees C and redisolve at 90 -100 degrees C.

There are various rarer conditions that can produce Bence Jones proteins, such as Waldenstrom’s macroglobulinemia.

Ans. C i.e. Ritumixab

Rituximab

• It is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells.
• Rituximab destroys B cells, and is therefore used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells.
• This includes many lymphomas, leukemias, transplant rejection, and autoimmune disorders.

Ans. d. Dose independent pharmacokinetics

Ans. is ‘c’ i.e., VEGF