New Genmab/Abbvie tie-up rings old bells

Followers of Nordic Nanovector and Oxford Biomedica, among others, will pay close attention to an early focus of yesterday’s deal.

Deals

For some seasoned biotech investors yesterday’s broad alliance between Genmab and Abbvie will have rung old bells. While its headline focus is on the anti-CD20 bispecific epcoritamab, behind the scenes lie two other projects against antigens with which some will be very familiar: CD37 and 5T4.

The former is perhaps most famous as being the target of Betalutin, an asset according to whose fortunes Nordic Nanovector’s stock has waxed and waned. 5T4, meanwhile, used to be a major focus of several Oxford Biomedica approaches, but was brought crashing to earth with the failure of Trovax’s pivotal Trist study in 2008.

The CD37 approach, too, has seen discontinuations. As is to be expected, Genmab and Abbvie insist that their bispecifics, DuoHexaBody-CD37 (GEN3009) and DuoBody-CD3x5T4, are “potentially best in class” (Genmab brings on Abbvie for bispecific boost, June 10, 2020).

GEN3009 is a bispecific MAb by virtue of engaging two different epitopes on CD37, and Genmab says this is a unique approach; after showing promise in vitro it is in a dose-escalation lymphoma study. DuoBody-CD3x5T4 is a T-cell-engaging bispecific, but an IND for it has only just been submitted.

Competition

There is more advanced industry work on the former antigen than the latter. In late 2016 Norway’s Nordic Nanovector touched a record valuation of $785m as Betalutin impressed in late-line lymphoma settings, but the realisation that work is still very early, coupled with delays, have caused the stock to drift since.

Betalutin comprises an unusual approach, combining CD37 targeting with the radionuclide lutetium-177; a follow-up uses lead-212 as the radionuclide.

Debiopharm’s naratuximab is a more typical antibody-drug conjugate, and was acquired from Immunogen three years ago; a phase II trial should end imminently. Among the disappointments are another ADC, from Seattle Genetics/Astellas, which was canned despite showing promise in heavily pretreated non-Hodgkin’s lymphoma in 2017.

Selected projects targeting CD37
Project Mechanism Company/institution Clinical trial?
Phase II
Naratuximab emtansine Anti-CD37 ADC Debiopharm (ex Immunogen) Rituxan combo in r/r lymphoma
Betalutin Anti-CD37 MAb-Lu-177 conjugate Nordic Nanovector Lymphoma trial with lilotomab (anti-CD37 MAb) pre-dosing
Phase I
GEN3009 Anti-CD37 dual-epitope MAb Genmab/Abbvie First-in-human lymphoma
CAR37 T Cells Anti-CD37 Car-T Massachusetts General Haem-onc trial yet to start enrolling
Preclinical
NNV013 Anti-CD37 MAb-Pb-212 conjugate Nordic Nanovector
Discontinued
Otlertuzumab Anti-CD37 MAb Aptevo Disc in Nov 2018 after lack of efficacy in T-cell lymphoma
AGS67E Anti-CD37 ADC Seattle Genetics/Astellas 30% ORR, 7/52CR
BI 836826 Anti-CD37 MAb Boehringer Ingelheim/Xencor 4 studies completed, 1 terminated, 1 withdrawn
Source: clinicaltrials.gov & EvaluatePharma.

Still, if some previous work on CD37 prompts doubts over the target, this is nothing compared with that on 5T4, a tumour antigen discovered by scientists at Cancer Research UK back in the 1990s.

5T4’s most notorious casualty was Oxford Biomedica’s Trovax, which crashed in phase III 12 years ago. To be fair this was a cancer vaccine, so its failure might have had more to do with the approach than the target, but Oxford has separately flirted with MAb, ADC and even Car-T formats against 5T4, none making significant progress.

A second big failure was Active Biotech’s anti-5T4 ADC Anyara, whose phase II/III renal cell carcinoma study blew up in 2013 (Anyara sounds the death knell for 5T4-targeted anticancers, January 29, 2013). Remarkably, Active managed to offload Anyara to Neotx, which is now running a phase I trial in combination with Imfinzi.

The precedent for targeting CD37 and 5T4 might not be great, but at least Genmab and Abbvie can boast novel approaches to hitting these old-school antigens. All that remains is for them to show their worth in the clinic.

Selected projects targeting 5T4
Project Mechanism Company/institution Clinical trial?
Phase II
VTP-800 Anti-5T4 cancer vaccine Vaccitech Opdivo combo in prostate cancer
Phase I
Anyara Anti-5T4 ADC Neotx (ex Active Biotech) Imfinzi combo; failed ph2/3 in renal cancer
Preclinical
DuoBody-CD3x5T4 Anti-5T4 bispecific MAb Genmab/Abbvie IND filed Q1 2020
ALG.APV-527 Anti-5T4/4-1BB bispecific MAb Alligator/Aptevo
OXB-302 Anti-5T4 Car-T Oxford Biomedica
UCART5T4 Anti-5T4 Car-T Cellectis
ASN004 Anti-5T4 ADC Asana/Mersana
Discontinued
Trovax-DC Anti-5T4 cancer vaccine Oxford Biomedica Failed ph3 Trist study
PF-06263507 Anti-5T4 ADC Oxford Biomedica/Pfizer
Source: clinicaltrials.gov & EvaluatePharma.

This story has been updated to include Vaccitech's VTP-800.

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