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Genmab's GEN1057

Targets: FAPα, DR4

Overview: GEN1057 (DuoBody-FAPαxDR4) is an investigational proprietary bispecific antibody created using Genmab’s DuoBody technology.

Clinical trials: A phase 1 clinical study of GEN1057 in malignant solid tumors is ongoing ( https://clinicaltrials.gov/study/NCT06573294?term=GEN1057&rank=1 ), started 28 Aug 2024.

Roche's FAP portfolio:

Roche perseveres with FAP ( https://www.oncologypipeline.com/apexonco/roche-perseveres-fap ), 1 Feb 2024 (LAST YEAR)

"The discontinuation today of the early-stage asset RG6189 would seem pretty ordinary – were it not for the fact that this is at least the third FAP-targeting project Roche had moved into the clinic and then terminated.

"The Swiss group has taken various attempts at hitting FAP (fibroblast activation protein α), a protease expressed in the tumour stroma, and not long ago its pipeline still boasted three separate anti-FAP assets. Only one of these now remains in development: Roche confirmed during its fourth-quarter results today that RG7827, a 4-1BB stimulating MAb, was continuing in phase 1, though this approach already has one black mark against it.

...

"So how will Roche fare with its currently final remaining FAP bet, RG7827? This uses 4-1BB co-stimulation to activate T cells in addition to hitting FAP, but as far as human data go Roche has only hinted at single-agent activity in a phase 1 case report in thymic carcinoma. The current development plan involves a combo with Roche’s anti-CEA T-cell engager cibisatamab, in a phase 1 colorectal cancer trial.

"However, not only has 4-1BB agonism so far disappointed as a bispecific MAb strategy, in FAP specifically it has one significant setback, with Amgen pulling out of a deal with Molecular Partners covering MP0310 (AMG 506) in 2022; this anti-FAP x 4-1BB darpin is now discontinued.

"Not only that, but Molecular Partners’ lead asset is another, wholly owned darpin, MP-317, which targets FAP and CD40 – the approach Roche has now ditched. FAP has gained notoriety of late for its promise as a target for radioligands, but it’s far from clear what potential it holds."

The key paragraphs from that Portuguese language news report:

"Along with these assets, Roche has removed the bispecific antibody RG7827 (4-1BBxFAP) from its portfolio, even though the company clarified that this decision is linked to the cancellation of the development of cibisatamab, its CEAxCD3 candidate. A company spokesperson explained that the interruption of the phase 1 study combining cibisatamab with FAP-4-1BBL does not imply that the development of FAP-4-1BBL in other contexts is completely abandoned.

"Last year, Roche continued the evaluation of cibisatamab together with its Tecentriq control point inhibitor in colorectal cancer, although at that time the company showed optimism about its potential in combination with other drugs. However, the company has taken the decision to progressively cease its support for this candidate.

"Roche's strategy reflects a restructuring of its oncology pipeline following several trials with less than encouraging results. Meanwhile, other companies continue to explore these same objectives. Molecular Partners continues to develop the bispecific FAPxCD40 MP0317, Novartis advances its radioligand therapies, and Genmab and Avacta Therapeutics maintain active development against FAP in phase 1."

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About RG7827 (4-1BBxFAP) mode of action:

(Google) AI Overview:

FAP-4-1BBL acts as a bispecific antibody that specifically targets and activates T cells only when it binds to both the Fibroblast Activation Protein (FAP) on cancer-associated fibroblasts and the 4-1BB receptor on T cells, essentially delivering a potent costimulatory signal to the T cell only within the tumor microenvironment, leading to enhanced T cell proliferation, activation, and cytotoxicity against cancer cells.

Key points about FAP-4-1BBL mode of action:

Targeted delivery:

By binding to FAP, which is highly expressed on cancer-associated fibroblasts, FAP-4-1BBL specifically delivers the 4-1BB agonist signal to the tumor site, minimizing off-target effects.

T cell activation:

Once bound to both FAP and 4-1BB, the FAP-4-1BBL complex triggers a strong costimulatory signal on the T cell, promoting its activation, proliferation, and differentiation into effector T cells.

Tumor-specific immune response:

This targeted activation allows for a robust antitumor immune response focused on the tumor microenvironment, potentially leading to improved efficacy with reduced systemic toxicity.

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Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer ( https://pmc.ncbi.nlm.nih.gov/articles/PMC7333869/ ), 2 Jul 2020

"Fibroblast activation protein (FAP)-targeted 4-1BBL (FAP-4-1BBL) induces secretion of interleukin (IL)-13 by CD4+ and CD8+ T cells which induces tumor cell apoptosis."

"But also could just hand it over to someone else to do all the work."

Would absolutely have to be licensed out for another company to do the development and regulatory work. Structure some licence agreement, e.g. non-exclusive or exclusive but time-limited in case the licencee doesn't progress development. Even license out by territory. Should be possible now with the available in vivo and clinical data and increased knowledge about FAP. It just seems like a very easy win for next to no effort ...if a research-orientated animal health company can be interested.

Don't forget the part AVA3996 has played in showing consistency of activity and thus proving the platform...

AVA6000: preclinical findings ✔️ clinical findings ✔️

AVA3996: preclinical findings ✔️

AVA6103: preclinical findings ✔️

@VS, of necessity, CEOs delegate.

Or not! That's the problem with only seeing the last few posts when people are posting a lot!

Apologies, wrong thread..

Email sent and delivery receipt received.

There's no guarantee that it is in her inbox and not in the junk folder but Alan read and replied to my emails so I'm hoping filtering hasn't since been applied.

I also specified a read receipt - will post if I receive one - but the man thing is that she sees the subject line in her inbox/junk folder and it's then up to her whether she opens the email.

Doxorubicin is one of the chemos used to treat cancer in cats and dogs. The chemo chosen depends on the cancer and how susceptible it is to the different modes of action of the chemos available, so doxorubicin isn't a catch-all.

An overview: https://todaysveterinarynurse.com/oncology/veterinary-doxorubicin/

I see no reason why AVA6000 couldn't or shouldn't be developed to be used in veterinary medicine as a kinder alternative to straight doxorubicin. We could push for this to be considered by Avacta but better, I think, to write to named individuals and the decision-makers at the top of the organisation, namely CC - chris.coughlin@avacta.com

If the emails get through, even if she only sees the subject then the message can get through. In that respect, a simple message subject mentioning the terms 'AVA6000' AND 'licensing' AND ('pets' OR 'veterinary' OR 'cats OR 'dogs') AND ('treatment' OR 'explore' OR 'possibility' OR etc.) would go a long way by just catching the eye

Example email subjects:

• Has licensing of AVA6000 for use in veterinary medicine been considered?

• Could AVA6000 be licensed out to treat pets?

• Is AVA6000 suitable for dogs? - Are there licensing possibilities there?

Any body of the message needs to be short, simple and to the point - she's a very busy person! - emphasising an aspect, e.g. 'kinder', 'more effective', 'easy revenue for Avacta', etc.

Be creative and compose your own version of subject and body!

Clearly another confused one. Confused by English.

I wasn't having a laugh. I was trying to explain the situation to the best of my ability for everyone's benefit.

(And for the avoidance of doubt, by 'Forget AVA6000', I meant just in this half-life context. It is clearly a drug with potential and is a lot closer to approval than any exatecan version.)

You seem confused. Forget AVA6000. It is what it is and it is far better than straight doxorubicin.

This article describes the exatecan half life problem nicely. Don't get all excited about the slow release mechanism; it's not targeted.

A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors ( https://pmc.ncbi.nlm.nih.gov/articles/PMC10208276/ )

"One of the limitations of current small-molecule TOP1i is their relatively short half-lives—the SN-38 formed from CPT-11 has an apparent t1/2 of approximately 12 hours (8) and Exa has a t1/2 of only approximately 10 hours in humans (12). As described above, effective suppression of TOP1 to cause DNA damage requires continuous presence of the inhibitor during S-phase of the cell cycle and inhibition of TOP1 is rapidly reversed upon drug withdrawal. Hence, the short half-lives of these TOP1i are suboptimal for drug efficacy, and extended-release forms of these agents are expected to show improved efficacy."

Interestingly, this part below mirrors what was found with AVA6103. Maybe this article was instrumental in kicking off the AVA6100/AVA6103 program (although there may have been other reports - this slow release-type title was just picked at random)...

"Remarkably, a single low dose of 10 μmol/kg PEG-Exa—only approximately 0.2 μmol/mouse—caused complete suppression of tumor growth of BRCA1-deficient MX-1 xenografts lasting over 40 days."

Https://www.aacr.org/meeting/aacr-annual-meeting-2025/key-dates/

Look at previous years' RNSes; none of us can know that; and Google AACR 2025.

Let us know what you find.

"No doubt someone will argue that wasn’t what CC actually said, but that was the point she was making and the reason for the modifications to produce AVA6103."

So what did she actually say about "AVA6000 has too short a half life to ensure that there is enough in the bloodstream at the time cancer cells are dividing. Said in latest video or words to that effect."

Tbf, eggy is a supertwat

Tbf, the full quote is "What's interesting about this one is on the left hand side where we stop treatment and we still continue with these complete regressions, we're seeing that in the clinic with AVA6000. And so patients who with salivary gland cancer who have essentially stopped treatment due to reaching the max level of cycles, they're continuing in these responses. Maybe it's a precision thing, something else that that we're all gonna have to figure out."

We knew it was already the case for AVA6000 with one patient that the cancer didn't progress when treatment stopped:

"• 79 yo male with SGC (ductal histology). Prior therapy: triptorelin/bicalutamide followed by disease progression

"• Enrolled in the AVA6000 trial (Oct 2023) in the 385 mg/m2 Q3W cohort; highest level of intratumoral doxorubicin of any patient at 24 hours post-dose

"• Confirmed partial response at 12 weeks; duration of response >18 weeks. Pt discontinued after reaching lifetime max of doxorubicin exposure; PR continuing in follow-up"

https://avacta.com/wp-content/uploads/2024/11/Avacta_RnD-Science-Day_30Oct2024_final-.pdf slide 42

She says patientS, so it could be they've found this in one or more other SGC patients since the data presented on Science Day.

There's nothing in yesterday's video that wasn't in the latest corporate deck released last Thursday.

There's a difference between predict and determine. One might predict the outcome of a sports match but it's not always a correct prediction. It is an educated guess based on 'known' facts, past experience, etc. One moves towards 'determine' as the probability of an outcome approaches 100% such as a ball released falling to the ground, or Liverpool beating an asthmatic pub team.