CD38-targeting antibodies: daratumumab

Question 1

What is the Jones protein and how was it discovered?

Answer 1

In 1844 Henry Bence Jones describes the urine of his patient: he found Jones protein: light-chain of Abs produced by the myeloma cells.

Question 2

What is the M protein?

Answer 2

M protein: monoclonal Ab produced by the myeloma cells (malignantly transformed plasma cells)

Question 3

What is melphalan?

Answer 3

Melphalan is a more recent treatment for multiple myeloma, but still a classic drug. It is an alkylating agent: it induces DNA crosslinks.

In 1958: Research in Russia by Blokhin, 3/6 patients responded to melphalan

In 1962: Daniel Bergsagel starts phase 2 studies in MD Anderson Houston, TX –> 3rd drug tested was melphalan: response in 8/24 patients

Question 4

Does prednisone improve melphalan treatment?

Answer 4

In 1969 Alexanian starts phase 3 study with melphalan vs. melphalan + prednisone
There was a survival benefit of 6 months for melphalan + prednisone.

Melphalan and Prednisone are standard of care for the next 40 years.

Question 5

What are more recent anti-myeloma drugs based on?

Answer 5

Patient features: age, co-morbidities, performance status.
Myeloma features: ISS, cytogenetics, LDH.
Previous therapy: response, duration, adverse events, did they have a transplant?

Question 6

What are IMIDs?

Answer 6

Immunomodulatory myeloma drugs. E.g.: thalidomide, lenalidomide, pomalidomide

Question 7

What are PIs?

Answer 7

Proteasome inhibitors. E.g.: Bortezomib, Carfilzomib, Ixazomib, Oprozomib

Question 8

What are alkylators/anthracyclins used for myeloma?

Answer 8

Melphan, Cyclophosphamide, Doxorubicin

Question 9

What are steroids used for myeloma?

Answer 9

Dexamethasone and Prednisone

Question 10

What are consolidation treatments for myeloma?

Answer 10

Consolidation treatments for myeloma:

Autologous stem cell transplantation, Allogeneic stem cell transplantation, Lymphocyte infusions

Question 11

What is the side chain theory and why is it relevant?

Answer 11

Paul Ehrlich had the first idea for a targeted drug. He formulated the side chain theory: Immune cells are dotted with receptors, each specific to a particular substance. When a toxin interacts with a receptor, the cell is activated and reacts by producing more receptors, which are released into the bloodstream as antibodies to neutralize the toxin.

Question 12

What is the target of Daratumumab?

Answer 12

an unique epitope of CD38, High expression on myeloma cells combined with its role in cell signaling suggest CD38 as a potential therapeutic Ab target for treatment of multiple myeloma (MM)

Question 13

How is daratumumab generated?

Answer 13

Human Ig transgenic mice were immunized with recombinant CD38 protein and CD38-transfected NIH 3T3. In this way they can make antibodies against human CD38. They then generated hybridomas (fusion of mice spleen/lymph node cells with SP2/0 MM cells). 42 anti-CD38 mAbs were tested in complement dependent cytotoxicity (CDC) assays. Only one mAb was capable to induce CDC and was selected for further testing: this was daratumumab

Question 14

What is the mechanism of action of immune-mediated activity of CD38?

Answer 14

Daratumumab binds to CD38, which results in the recruitment of NK cells. Fc tail of the Ab binds to Fc receptor on NK cells. Nk cells then kill the tumour cell. –> antibody-dependent, cellular cytotoxicity.
o Fc tail can bind to macrophages: antibody-dependent, cell-mediated phagocytosis
o The Fc tail can bind to C1q, the first component of the complement pathway –> complement-dependent cytotoxicity
o Ab can directly induce apoptosis/growth arrest via targeting of signaling pathways

Question 15

How do patients respond to daratumamab?

Answer 15

It works, there is 35-100% reduction of tumour load

Question 16

What is the direct anti-tumour effect of daratumumab?

Answer 16

Apoptosis via crosslinking

Question 17

What is the immunomodulation effect of daratumumab?

Answer 17

Immunomodulation effect of daratumumab:
Decreased immunosuppression: Targets CD38+ Tregs, Bregs and MDSCs that normally inhibit CD8+ T-cells

CD38 enzymatic inhibition: It blocks NAD, which stops the secretion of adenosine. Normally, adenosine inhibits CD8+ T-cells

Question 18

Are combinations with daratumamab useful?

Answer 18

Combination will prevent to outgrowth of resistant clones, prevent relapse and improve survival

Question 19

What are drugs that can be combined with daratumamab?

Answer 19

Lenalidomide:
o Immunomodulatory drug with direct effects and activation NK cells and T-cells, inhibition Tregs and endothelial cells (which play a role in angiogenesis)
o Ex vivo: synergistic with Daratumamab
o In vivo: mice: combination better at reducing tumour growth than either compound alone.
o In vivo: clinical trials: progression-free survival significantly better! (83% vs. 60%)
o Approved as combination therapy!

VTD:
o Progression-free survival much better with daratumamab-VTD, then with VTD alone.
o FDA/EMA approval!

Question 20

In what other cancers can daratumamab be used?

Answer 20

CD38+:
o Lymphoma
o Acute myeloid leukemia: trials are still ongoing

CD38-:
o Used as an immune-modulater instead of CD38 target. It can improve T-cell response of the patient, but no direct effects on the tumour
o CLL
o ALL
o AML