It might just be coincidence, but it won’t go unnoticed that Amgen upping its game in bispecific antibodies came just a day after Novartis moved to close its cell and gene therapy division, prompting doubts over the Swiss firm’s commitment to CAR-T therapy.
After all, bispecifics work in a broadly similar way to CARs but use a far simpler approach, and while efficacy is less impressive they are seen by some as an underappreciated threat to CAR-T. Amgen buying Boehringer out of a BCMA-targeting bispecific yesterday threatens Bluebird and Celgene, and there are plenty more assets in the pipeline (see table below).
Boehringer’s involvement in BI 836909 dates back to a 2010 multiple myeloma deal it had struck with Micromet, though it was, until yesterday, not widely known that the asset in question targeted BCMA. In 2012 Amgen acquired Micromet for $1.6bn, and yesterday it bought out Boehringer’s interest for an undisclosed amount.
Micromet brought with it blinatumomab, which Amgen launched two years ago as Blincyto for adult ALL, and yesterday the group delivered a second punch of bispecific progress, announcing additional Blincyto approval for paediatric ALL.
Like CARs but different
While CAR-T therapy is based on genetically engineering patients’ T cells to express a chimaeric protein that targets a specific antigen, bispecifics are artificial antibody-based constructs that target both the desired antigen and, in the case of T-cell recruiting projects, CD3, a protein present on effector T cells.
The idea is to bring existing T cells into close proximity with target tumour cells, form an immunological synapse and bring about cell-mediated lysis. Thus Blincyto, a CD19/CD3 bispecific, is analogous to CD19-directed CARs such as Kite’s KTE-C19, Novartis’s CTL019 or Juno’s JCAR015.
The idea with BI 836909, which Amgen now calls AMG 420 (and in its statement refers to, perhaps erroneously, as BI 836908) is the same. BCMA is an antigen present on plasma cells – hence its relevance in multiple myeloma – and the most prominent anti-BCMA CAR project is Bluebird/Celgene’s bb2121.
While the experience with anti-CD19 approaches shows CARs strongly outpacing bispecifics in terms of initial remission rates, complexity of manufacturing and eventual pricing will play an important part. Moreover, a Blincyto patient relapsing through CD19 antigen escape would no longer be a candidate for an anti-CD19 CAR.
Resistance mechanisms are different for each antigen, and work with BCMA is too early to tell whether antigen escape might be a problem. Michael Gladsonte, principal with Atlas Venture, tells EP Vantage that BCMA, a relatively small protein, is in any case a very tough target to hit with an antibody.
Nevertheless, enthusiasm for this and other bispecifics is growing, as evidenced by the list of competitive industry projects, many of which hit the same antigen targets as CAR-T (EHA – CAR-T has Blincyto breathing down its neck, June 13, 2016).
|A selection of bispecific MAbs for oncology indications*|
|Project||Company||Target antigen||Type||Trial ID||Lead indication|
|MGD011||Johnson & Johnson/Macrogenics||CD19||Dart||NCT02454270||Leukaemia/lymphoma|
|JNJ-63709178||Johnson & Johnson/Genmab||CD123||Hybrid MAb||NCT02715011||AML|
|RO6958688||Roche||CEA||Not disclosed||NCT02324257||Solid tumours|
|ERY974||Chugai Pharmaceutical||GPC3||Not disclosed||NCT02748837||Solid tumours|
|GBR 1302||Glenmark Pharmaceuticals||Her2||Hybrid MAb||NCT02829372||Her2-expressing solid tumours|
|DuoBody Research Project||Genmab||CD20||Hybrid MAb||–||Haematological cancers|
|XmAb13676||Novartis/Xencor||CD20||Bispecific Fc||–||Haematological cancers|
|(E1)-3s||Immunomedics||Trop2||Hybrid MAb||–||Epithelial cancers|
|Anti CD3 X CD38 MAb Program||Amgen/Xencor||CD38||Bispecific Fc||–||Multiple myeloma|
|*Excludes projects that do not recruit T cells through binding CD3. Source: EvaluatePharma.|
Within the above list lie several distinct approaches to generate bispecific targeting. Thus Genmab’s duobodies comprise the linked halves of two distinct MAbs, while Affimed’s Tandabs, Macrogenics’ Darts and Micromet’s Bites are made up of various portions of just the binding regions of a typical antibody.
And beyond there are other bispecific proteins, such as those targeting two epitopes, or those designed to activate other cell types, such as antigen-presenting cells – Abbvie’s CD40-binding ABBV-428 – or natural killer cells – Affimed’s CD16-binding AFM13. The indications also stretch beyond oncology – witness Roche’s haemophilia project emicizumab, a factor IXa/X bispecific.
Of course, there have been problems; the honour of being the first bispecific to hit the markets belongs not to Blincyto but to Trion Pharma’s Epcam/CD3 bispecific, Removab, launched in Europe in 2009 for malignant ascites. Removab fell by the wayside when Trion folded in 2013, and so did the clinical-stage projects Lymphomun (CD20/CD3) and ertumaxomab (Her2/CD3).
However, these setbacks have not thrown much of a spanner into the works and, with the likes of Amgen, Johnson & Johnson and Novartis making big bets on bispecifics, the game is on.