non-Hodgkin lymphoma

Disease ID:1219
Name:non-Hodgkin lymphoma
Associated with:2 targets
1 immuno-relevant target
7 immuno-relevant ligands
Description
A lymphoma that is characterized as any kind of lymphoma except Hodgkin's lymphoma.
Database Links
Disease Ontology: DOID:0060060
OMIM: 605027

Targets

CD20 (membrane-spanning 4-domains, subfamily A, member 1)
Comments:  CD20 is the molecular target of the B cell NHL therapeutic ibritumomab tiuxetan.
Ligand interactions: 
Ligand Comments
ibritumomab tiuxetan
Approved specifically for relapsed or refractory, low grade or transformed B cell non-Hodgkin's lymphoma can be treated with Yttrium-90 labelled ibrit ...
tositumomab
Approved for CD20 positive follicular non-Hodgkin's lymphoma but production/sales were ceased by the manufacturer in 2014.
CD37 molecule
Comments:  CD37 is an immuno-oncology target that is being expoited for the development of novel therapeutics for the treatment of B cell lymphomas.
References:  9
Ligand interactions: 
Ligand Comments
otlertuzumab
Phase 1 clinical candidate for NHL- see NCT00614042 and NCT01317901.
lilotomab
A first-in-human phase 1/2a study for relapsed CD37+ve indolent NHL determined that predosing with 'cold' lilotomab resulted in a more favourable rati ...

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
plerixafor
Immuno Disease Comments: Immunostimulant stem cell mobiliser used in autologous stem cell transplantation.
Clinical Use: Plerixafor is an immunostimulant approved for use as a hematopoietic stem cell mobiliser in the treatment of non-Hodgkin lymphoma and multiple myeloma where autologous stem cell transplantation is necessary. The EMA granted plerixafor orphan status in 2011 as an adjunctive treatment to cytotoxic therapy in acute myeloid leukaemia.

Recent studies have suggested the possibility of plerixafor being repurposed for new indications, including recurrent high-grade glioma and pancreatic cancer. Plerixafor is in Phase I study (in combination with ) for recurrent high-grade glioma (ClinicalTrials.gov identifier NCT01339039). | View clinical data
IL-2
Immuno Disease Comments: US FDA orphan designation only, not approved for this indication.
Clinical Use: Aldesleukin is US FDA approved to treat metastatic renal cell carcinoma. The FDA has also granted orphan designation for non-Hodgkin's lymphoma (1998), primary immunodeficiency disease associated with T-cell defects (1989) and metastatic melanoma (1996). The EMA's orphan designation for renal cell carcinoma was withdrawn by the drug's sponsor. | View clinical data
idelalisib
Immuno Disease Comments: Approved specifically for relapsed follicular B-cell non-Hodgkin lymphoma.
Clinical Use: Idelalisib is a treatmet for difficult to treat leukemia and lymphomas. The potential of this drug was highlighted by the early termination of a phase 3 clinical trial, so that all participants could be given the drug [2]. Idelalisib was approved in July 2014, for patients with relapsed chronic lymphocytic leukemia (CLL), in combination with . The FDA also granted the drug accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), particularly indicated for patients who have received at least two prior systemic therapies.

To view a full list of trials registered with ClinicalTrials.gov assessing idelalisib, click here. | View clinical data
ibritumomab tiuxetan
Immuno Disease Comments: Approved specifically for relapsed or refractory, low grade or transformed B cell non-Hodgkin's lymphoma can be treated with Yttrium-90 labelled ibritumomab tiuxetan.
Clinical Use: Used to treat relapsed or refractory, low grade or transformed B cell non-Hodgkin's lymphoma (labelled with the high energy beta emitter, Yttrium-90). Can be labelled with Indium-111 for diagnostic investigation/imaging. | View clinical data
Bioactivity Comments: The labelled antibody shows high affinity and selectivity for its target antigen [1]. We have been unable to find affinity data for the interaction between this antibody and CD20 in any open access article. | View biological activity
tositumomab
Immuno Disease Comments: Approved for CD20 positive follicular non-Hodgkin's lymphoma but production/sales were ceased by the manufacturer in 2014.
Clinical Use: Used to treat CD20 positive follicular non-Hodgkin's lymphoma. Has orphan drug designation by EMA for use to treat follicular lymphoma.
Unfortunately GlaxoSmithKline, the drug's manufacturer ceased production and sales of tositumomab in early 2014. The drug was clinically highly efficacious, but confounding market-driven factors lead to its commercial failure. Iinitial regulatory delays, manufacturing problems (on the radioactive component side), strong competition (new types of drugs for non-Hodgkin's lymphoma coming through the development pipeline, eg ), insufficient reimbursement by medical insurers and issues around physician referral patterns all influenced the decision to withdraw this drug from the market. | View clinical data
Bioactivity Comments: We have been unable to find any publicly available affinity value for the interaction between tositumomab and its antigen, CD20. The patent covering the use of radioactively-labelled anti-CD20 antibodies [4] refers back to articles and abstracts published in the early 1980's [3,7], none of which provide affinity data. | View biological activity
otlertuzumab
Immuno Disease Comments: Phase 1 clinical candidate for NHL- see NCT00614042 and NCT01317901.
Clinical Use: Preliminary evidence of clinical efficacy in a small number of patients with highly refractory, heavily pretreated B-cell non-Hodgkin lymphoma has been reported [5]- see NCT00614042. A Phase 1b study of TRU-016 plus other biological or small molecule chemotherapeutic drugs (NCT01644253) is under way (May 2018). | View clinical data
Bioactivity Comments: Rafiq et al. (2013) [6] show a dose-respnse curve of TRU-016 binding to CD37 on Daudi cells (with the x axis labeled as 'ng/well' rather than as a defined molarity), but do not present a calculated affinity constant. | View biological activity
lilotomab 8
Immuno Disease Comments: A first-in-human phase 1/2a study for relapsed CD37+ve indolent NHL determined that predosing with 'cold' lilotomab resulted in a more favourable ratio of labelled lilotomab being adsorbed to tumour cells rather than to red marrow (which is a dose-limiting site of biodistribution for 177Lu-lilotomab satetraxetan treatment).
Clinical Use: Click here to link to a complete list of lilotomab clinical studies that are registered at ClinicalTrials.gov. | View clinical data

References

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1. Chinn PC, Leonard JE, Rosenberg J, Hanna N, Anderson DR. (1999) Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin's lymphoma. Int. J. Oncol., 15 (5): 1017-25. [PMID:10536187]

2. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I et al.. (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med., 370 (11): 997-1007. [PMID:24450857]

3. Greenberger JS, Rothstein L, DeFabritiis P, Bregni M, Bast Jr R, Ritz J, Nadler LM, Lipton JM, Sakakeeny MA. (1985) Effects of monoclonal antibody and complement treatment of human marrow on hematopoiesis in continuous bone marrow culture. Cancer Res., 45 (2): 758-67. [PMID:3967246]

4. Kaminski MS, Butchko GM, Glenn SD, Wahl RL. (1998) Radioimmunotherapy of lymphoma using anti-CD20 antibodies. Patent number: US5843398. Assignee: Coulter Pharmaceutical, Inc., Regents Of The University Of Michigan. Priority date: 16/09/1993. Publication date: 01/12/1998.

5. Pagel JM, Spurgeon SE, Byrd JC, Awan FT, Flinn IW, Lanasa MC, Eisenfeld AJ, Stromatt SC, Gopal AK. (2015) Otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR(™) therapeutic protein, for relapsed or refractory NHL patients. Br. J. Haematol., 168 (1): 38-45. [PMID:25146490]

6. Rafiq S, Siadak A, Butchar JP, Cheney C, Lozanski G, Jacob NK, Lapalombella R, McGourty J, Moledor M, Lowe R et al.. (2013) Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies. MAbs, 5 (5): 723-35. [PMID:23883821]

7. Stashenko P, Nadler LM, Hardy R, Schlossman SF. (1980) Characterization of a human B lymphocyte-specific antigen. J. Immunol., 125 (4): 1678-85. [PMID:6157744]

8. Stokke C, Blakkisrud J, Løndalen A, Dahle J, Martinsen ACT, Holte H, Kolstad A. (2018) Pre-dosing with lilotomab prior to therapy with 177Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients. Eur. J. Nucl. Med. Mol. Imaging, 45 (7): 1233-1241. [PMID:29470615]

9. Witkowska M, Smolewski P, Robak T. (2018) Investigational therapies targeting CD37 for the treatment of B-cell lymphoid malignancies. Expert Opin Investig Drugs, 27 (2): 171-177. [PMID:29323537]