There cur­rently are more than 300 clin­i­cal trials ongoing around the world that are investigating treat­ments for multiple myeloma and looking for patient par­tic­i­pants. Most of these trials are exploring new myeloma ther­a­pies that have not yet been approved for use outside of clin­i­cal trials, and many of these “investigational” ther­a­pies, as they often are called, have the poten­tial to be extremely effective.

The number of new treat­ments under devel­op­ment for multiple myeloma is greater than it ever has been, and this creates tremendous hope in the myeloma com­munity. In just a few years, a number of new drugs are likely to be approved for the treat­ment of myeloma, and patients have the option of exploring many of those options now by par­tic­i­pating in clin­i­cal trials.

At the same time, the ex­panding number of poten­tial treat­ments for multiple myeloma makes it dif­fi­cult to stay informed about all the dif­fer­en­t options. For this reason, The Myeloma Beacon is starting a new “Getting To Know” series of occasional articles to introduce myeloma patients and care­givers to treat­ments physicians and researchers are investigating.

In this, the first of the “Getting To Know” series, the focus is on a drug known as TNB-383B.

TNB-383B: A Bispecific Antibody Targeting BCMA And CD3

TNB-383B is an in­fused drug that is just starting clin­i­cal trial testing. Like the approved myeloma ther­a­pies Darzalex (dara­tu­mu­mab) and Empliciti (elotuzumab), TNB-383B is a mono­clonal anti­body. TNB-383B differs from the two approved mono­clonal anti­body myeloma ther­a­pies, how­ever, in several im­por­tant ways.

First, Darzalex and Empliciti work by targeting one specific protein found on myeloma cells. In the case of Darzalex, the targeted protein is known as CD38. In the case of Empliciti, the targeted protein is SLAMF7 (also known as CD319 and CS1).

TNB-383B, on the other hand, targets two proteins: BCMA (an abbre­vi­a­tion for “B-cell maturation an­ti­gen”) and CD3. Mono­clonal anti­bodies like TNB-383B that have two targets often are called “bispecific anti­bodies.”

In the body, BCMA is found mainly on myeloma cells, and the initial step in the way TNB-383B is designed to work is by attaching itself to the BCMA on myeloma cells.

Once a TNB-383B molecule is attached to a myeloma cell, the drug’s second target, CD3, comes into play. The CD3 attracts and then binds T-cells to the drug and to the myeloma cell, after which the T-cells attack and, if all goes well, kill the myeloma cell.

Another Bispecific Antibody Targeting BCMA And CD3: AMG 420

TNB-383B is not the only BCMA- and CD3-targeting bispecific anti­body being tested as a poten­tial new treat­ment for multiple myeloma. There are, in fact, several. The best known of them is AMG 420 (BI 836909), cur­rently under devel­op­ment by Amgen. Results of AMG 420’s Phase 1 clin­i­cal trial have been presented at medical conferences as recently as this past summer.

Patients in the Phase 1 trial of AMG 420 had a median of 4 prior lines of ther­apy, and all had been treated with at least one immuno­modu­la­tory drug like Revlimid (lena­lido­mide) or Pomalyst (poma­lido­mide, Imnovid) and at least one pro­te­a­some in­hib­i­tor, such as Velcade (bor­tez­o­mib) or Kyprolis (car­filz­o­mib). About a quarter of the patients had been treated at some point with Darzalex.

Among the 10 patients in the Phase 1 trial who were given the dose of AMG 420 that is going to be tested in future trials of the drug, seven (70 per­cent) achieved at least a partial response, and five (50 per­cent) became minimal residual dis­ease neg­a­tive. Myeloma specialists generally have been im­pressed by these responses given how heavily pre­treated the patients in this trial were.

TBN-383B’s Unique Structure

TNB-383B differs somewhat from AMG 420, how­ever, in a way that also dif­fer­en­ti­ates the drug from Darzalex and Empliciti.

In particular, TNB-383B consists of two immuno­glob­u­lin heavy chains and just one immuno­glob­u­lin light chain, as depicted in Figure 1 above. Darzalex and Empliciti, in contrast, have the standard two heavy and two light chains one ex­pec­ts in immuno­glob­u­lin molecules (similar to part (a) of Figure 2, below). AMG 420 consists of the com­bined heavy chain and light chain tips of two dif­fer­en­t anti­bodies fused together (Figure 2).

TNB-383B’s structure is relevant primarily in terms of what its efficacy and safety may be like in comparison to a drug like AMG 420 that also targets both BCMA and CD3. The fact that the TNB-383B molecule has two full immuno­glob­u­lin heavy chains means it could stay longer in patient’s bodies, in­creas­ing its efficacy. The drug’s developers also believe TNB-383B’s design could reduce how likely it is to cause the side effect known as cytokine release syn­drome, a poten­tially serious immune sys­tem reac­tion that has occurred in AMG 420 and other ther­a­pies that affect the immune sys­tem.

It is worth noting that, in addi­tion to AMG 420, several other well-known inves­ti­ga­tional ther­a­pies for multiple myeloma are targeting the BCMA protein, in­clud­ing the CAR T-cell ther­apy bb2121 and the anti­body-drug con­ju­gate be­lan­ta­mab mafo­dotin (GSK2857916).

The Phase 1 Trial Testing TNB-383B In Multiple Myeloma

There cur­rently is one clin­i­cal trial underway exploring the efficacy and safety of TNB-383B in multiple myeloma patients. It is a Phase 1 trial in­tended, in part, to estab­lish­ the optimal dose of the drug. The trial is taking place in the United States, and it eventually will be open to patients at a minimum of six dif­fer­en­t locations. Two locations, one in North Carolina and one in Wisconsin, already are enrolling patients.

To par­tic­i­pate in the TNB-383B trial, patients must have re­lapsed multiple myeloma, and they must pre­vi­ously have been treated with an immunodulatory ther­apy, a pro­te­a­some in­hib­i­tor, and a CD38-targeted ther­apy.

Immunodulatory ther­a­pies in­clude Revlimid (lena­lido­mide), Pomalyst (poma­lido­mide), and thalido­mide. Proteasome in­hib­i­tor ther­a­pies in­clude Velcade (bor­tez­o­mib), Kyprolis (car­filz­o­mib), and Ninlaro (ixazomib). CD38-targeted ther­a­pies in­clude Darzalex and the inves­ti­ga­tional agent isatuximab.

More details about the TNB-383B trial, in­clud­ing trial locations and eligibility criteria, can be found at the trial’s page at clin­i­caltrials.gov.

The Com­panies Developing TNB-383B

TNB-383B is being devel­oped through a col­lab­o­ration involving two com­pa­nies, TeneoBio and AbbVie. Neither of those com­pa­nies have provided financial or any other form of sup­port or com­pen­sa­tion to The Myeloma Beacon or its employees. To ensure the objectivity of the in­for­ma­tion it pro­vides the myeloma com­munity, The Beacon neither seeks nor accepts financial sup­port from pharma­ceu­tical com­pa­nies or or­ga­ni­za­tions sup­ported by them.