Good things come in 3s - Wave 2
A post-ASCO update on tumor targets DLL3, B7H3 and Her3
June 2025
Paul D Rennert, SugarCone Biotech LLC
Introduction: DLL3, B7H3 and Her3 are compelling tumor antigens to target with cancer therapeutics. They have interesting patterns of expression in different cancer indications; thus, diverse therapies for attacking these targets have been developed. Each target and each therapeutic modality induces varying degrees of clinical efficacy, as well as causing toxicities. Importantly, effective combinatorial approaches that include these targets are emerging. Finally, while there are clear front runners among the pharmaceutical companies developing targeted therapeutics for these antigens there are also emerging biotechs aggressively pursuing these targets. The result is a complex clinical, commercial and competitive landscape.
Let’s dive in…
Wave 2: B7-H3
Optimistically named B7-homologue-3, B7-H3, a distant relative of the immune regulatory proteins B7-1 and B7-2, has recently moved into the spotlight - not as an immune regulator but as a target of advanced therapeutic modalities including bispecific antibodies, antibody drug conjugates (ADC) and CAR-T cells. As we’ll see, ASCO 2025 was a breakout conference for B7-H3-targeted therapies.
B7-H3 is a notable protein target for cancer due to its high level of expression on many important tumor types but generally low or absent expression in most normal tissues.
B7-H3 is overexpressed in a broad range of malignancies, including prostate, breast, lung, pancreatic, colorectal, lung, bladder and ovarian cancers. High B7-H3 expression levels have been linked to advanced tumor stages, metastasis, and poor prognosis in several cancers. Expression on normal cells is seen within the immune system on activated lymphocytes and myeloid cells and in other cell types like adipocytes. In all normal cells, expression is much lower than on cancerous cells.
We saw in part 1 that the most advanced therapies for targeting DLL3 were bispecific antibodies (Wave 1 - DLL3). Advanced therapies targeting B7-H3 use different modalities, currently dominated by ADCs. The sheer number of programs creates a complex and competitive landscape on top of the diverse clinical applications being tested. No B7-H3-directed therapeutics have received FDA or other approvals yet but the wave is building, especially with ADCs.
ADC: Antibody-Drug Conjugates
First it is important to put this wave of drug development into perspective. There are currently 53 active programs visible in the Beacon Intelligence database, and 37 of these are preclinical programs. We sense a pile-on effect here, as companies rush in with programs following compelling clinical results. This “lemming” stampede is similar to what we saw with the PD-(L)-1 x VEGF class (link).
Regardless, there are some clear leaders in this space:
Note the emphasis on several indications, notably SCLC and CRPC. It has been reported that 65% of SCLC tumors expressed moderate to high B7-H3 levels and >90% of CRPC biopsies (93%) expressed B7-H3 at the time of diagnosis. B7-H3 is highly overexpressed in the other cancers shown in the table including esophageal cancers (adenocarcinomas and squamous cell carcinomas) and gynecologic cancers (ovarian, cervical, and endometrial).
The headliner in the B7-H3 ADC space, ifinatamab deruxtecan, aka I-DXd, has led the way in these indications, and has set the baseline for early efficacy. Merck and Daiichi Sankyo have dosed their first patients in two randomized Phase 3 trials: the IDeate-Lung02 study in relapsed SCLC and the IDeate-Esophageal01 study in patients with unresectable advanced or metastatic esophageal squamous cell carcinoma. Early results shown in the preceding table suggest that the programs chasing I-DXd are showing comparable rates of ORR and PFS and these programs are advancing in Phase 2 and Phase 3 studies.
It is striking that four of the clinical programs feature Western/APAC partnerships – Merck/Daiichi Sankyo, GSK/Hansoh, AZN/Medilink, and Duality Bio/BioNTech. Globally, there are a least another 10 companies in the clinical already.
Merck has been foreshadowing development plans for I-DXd. At their ASCO 2025 investor event they positioned I-DXd alongside gocatamig (their DLL-3 x CD3 bispecific) for the treatment of SCLC:
A second combination being advanced by Merck and Daiichi pairs I-DXd with a second ADC, Raludotatug deruxtecan, that targets CDH6. That trial is in second-line NSCLC. Critical readouts will include the safety and tolerability of these combinations.
The move by Merck and Daiichi to advance these drugs in combination parallels an important move in the ADC space - the development of bispecific ADCs. Most programs are preclinical, but it is worth looking at this landscape just to see the breadth of combinatorial ADC development involving B7-H3. Examples are shown in the table (there are a total of 15 such programs visible in the Beacon Intelligence databases).
As with the I-DXd/gocatamig ADC + bispecific duo, the key for these diverse bispecific ADC programs will be the balance of efficacy with toxicity.
Other therapeutic classes
The appearance of bispecific ADCs leads to a broader view of the bispecific space targeting B7-H3. Surprisingly few CD3 x B7-H3 programs are visible here. TAK-280 was a protease-activated TCE prodrug therapeutic being developed by Takeda but has been dropped. Several preclinical programs have been declared by BioAlta/Himalaya, ExcelMab, and Helixon. Xencor and Janssen are developing a CD28 x B7-H3 TCE but this is a bispecific format that has yet to produce notable efficacy regardless of the tumor antigen targeted.
This raises an interesting question. In the last post we looked at the DLL3-targeting therapeutic space, dominated by bispecific programs in SCLC. Here we are looking at B7-H3, a target that is also prominent in SCLC. Perhaps the opportunity here to advance a B7-H3 x CD3 bispecific is being missed? Keeping an eye on the preclinical programs as they advance seems warranted. We may also look for programs advancing B7-H3-targeted therapies with immune checkpoint inhibitors.
We come next to another interesting question: how are different therapeutic modalities matched to indications? The ADCs reviewed above show clear indication bias for SLCL and CRPC. The cell therapy space is very different and dominated by B7-H3-directed CAR-T cells targeting CNS cancers, specifically glioblastoma and the pediatric primary brain cancers. Here the infusion of the cell therapy can be localized or systemic and the academic literature is rich in provocative papers describing routes of infusion, levels and duration of CAR T cell expansion and preliminary efficacy signals. Companies have been slower to join this race, as the challenge of these indications is enormous. Among companies in this space is our own Aleta Biotherapeutics and also Brainchild Bio, Elpis Biopharmaceuticals, and T-Maximum.
Stay tuned.
Next up --- Wave 3: The Ankle Biter
Targeting Her3 – a surprising growth factor receptor
