The latest entrants are Kolen Biotech and Crescent. Recently, the two companies reached a unique licensing agreement, mutually introducing each other's core pipeline assets and jointly joining the PD-1/VEGF+ADC development camp.

The collaboration between Kelun Biotech and Crescent can be seen as a small and medium-sized player quickly following the lead of giants in this game. Core players such as BioNTech/BMS, 3SBio/Pfizer are laying out their strategies and competing in this field. It is not difficult to see from their clinical development strategies that the combination of PD-1(L1)/VEGF bispecific antibodies and ADCs is upgrading from "exploration" to "standard".

Just a few months ago, global pharmaceutical companies were hunting down PD-(L)1/VEGF bispecific antibodies, driving up the prices of these assets. Now, with the trend of PD-(L)1/VEGF bispecific antibodies accelerating their iteration into monoclonal antibodies confirmed, MNCs have been aggressively pursuing these acquired assets, and the "battleground" has shifted to the competition of next-generation IO+ADCs.

In the era of single-drug therapy, speed was key; in the era of collaborative therapy, speed is important, but so is synergy. Everything is just beginning.

01
Kolenbote and Crescent each get what they need.

The collaboration between Kelun Biotech and Crescent can be described as a precise strategic move that "gets what they need." Looking at the core of the deal, the two companies swapped rights to two key drug candidates, filling gaps in their respective pipelines and laying the groundwork for future combination therapies.

According to the terms of the collaboration, Kelun Biotech licensed the overseas rights (markets outside the United States, Europe and Greater China) of its ADC SKB105 targeting integrin β6 (ITGB6) to Crescent, while Crescent exclusively granted Kelun Biotech the Greater China rights to its PD-1/VEGF bispecific antibody CR-001.

Kolentech will receive an upfront payment of $80 million, plus milestone payments and sales royalties of up to $1.25 billion; in return, Kolentech will pay Crescent an upfront payment of $20 million, plus milestone payments and sales royalties of up to $30 million.

In addition, if Crescent undergoes a change of control or enters into a sublicensing agreement, Kelunbote can receive additional payments, and both parties have the right to independently develop solutions for combining CR-001 with their respective ADC pipelines.

Crescent follows a fast-follow approach, with its core project CR-001 sharing the same design as AK112. However, in the current era of PD-1(L1)/VEGF combined with ADC for acceleration, a single PD-1(L1)/VEGF dual-antibody is far from sufficient.

With the acquisition of SKB105, Crescent not only gains a differentiated ADC asset, but also benefits from its proprietary Kthiol® irreversible conjugation technology, which combines a topoisomerase I inhibitor payload. SKB105 has demonstrated promising efficacy, safety, and pharmacokinetic characteristics in preclinical studies. Furthermore, ITGB6 is highly expressed in various solid tumors but lowly expressed in normal tissues, reducing systemic toxicity and off-target risks. This ADC acquisition also paves the way for subsequent combination therapies. According to Crescent's plan, SKB105 and CR-001 will first undergo Phase I/II monotherapy clinical trials, with combination therapy studies to follow in the first half of 2027.

For Kolen Biotech, this "reverse" import of the CR-001 is equally significant.

Previously, Kelun Biotech had established collaborations with MNCs such as Merck with multiple ADC assets, but its oncology pipeline lacked a key immunotherapy asset: a PD-1/VEGF bispecific antibody. The addition of CR-001 not only fills this gap but also creates synergies with its existing ADC pipeline, further exploring the clinical value of ADC assets and positioning itself in the next-generation IO+ADC wave.

02
PD-1/VEGF + ADC become standard configuration

Before the entry of companies like Kolenbote and Crescent, PD-1/VEGF + ADC had become the core strategy for major players in the PD-1/VEGF dual-resistance track.

BioNTech was the first to propose this strategy, with its "Establish, Expand, Elevate" three-step development strategy. The "Elevate" strategy is aimed at the next generation of combination therapies, promoting the combination of BNT327 with ADCs targeting HER2, B7-H3, Trop2, and other targets.

Currently, Phase 1/2 clinical trials of BNT327 in combination with HER2 ADC (BNT323/DB-1303), B7-H3 ADC (BNT324/DB-1311), Trop2 ADC (BNT325/DB-1305), and novel immune target drugs (such as the PVRIG inhibitor BNT3213) have begun enrolling patients for multiple indications, including breast cancer, hepatocellular carcinoma, and malignant mesothelioma.

As a pioneer in the PD-1/VEGF bispecific antibody field, Akeso Biopharma has also launched clinical trials for ADC combination therapy. In August of this year, AK112 initiated its first combination ADC clinical trial, in conjunction with Yilian Biopharma's B7H3 ADC drug YL201, in a Phase I/II trial for patients with solid tumors. Earlier, Yilian Biopharma's HER3 ADC drug had already initiated a clinical trial in combination with BioNTech's PD-L1/VEGF bispecific antibody therapy.

Following its acquisition by 3SBio, Pfizer quickly ramped up its efforts, releasing a three-step strategy: "Displace, Establish, Expand." "Establish" specifically refers to the plan to explore the combination of PF-08634404 and ADCs across different treatment lines, thereby establishing a new generation of "chemotherapy-free" regimens.

On November 12, it registered a Phase 1/2 clinical trial (NCT07227298) on the ClinicalTrials website for 4404 in combination with the integrin β6 ADC drug Sigvotatug Vedotin, with an expected start date of November 2025. This is the first clinical trial of 4404 in combination with an ADC.

Pfizer has publicly stated that it will not follow the clinical development of AK112 in lung cancer, but will instead build its competitiveness through differentiated approaches such as combining it with ADCs. Furthermore, as the latest entrant into the field, Pfizer's development strategy primarily emphasizes "speed," relying on its strong global development capabilities to catch up with the schedule.

Intriguingly, earlier this year, Pfizer reached a combination therapy agreement with Summit, a partner of Akeso Biopharma, to explore the synergistic potential of AK112 with its ADC drug. However, just a few months later, Pfizer made a significant bet on 3SBio with an initial payment twice that of the Akeso deal.

It is not hard to see that PD-1/VEGF+ADC has quickly transformed from a concept into a battleground for core players and has become an industry-recognized standard for research and development.

03
Striving for the next commanding heights

The accelerated entry of MNCs like Pfizer and BMS, along with biotechs like Kelun Biotech and Crescent, is essentially a global pharmaceutical company's struggle for dominance in next-generation combination therapy. As BioNTech stated, they hope to leverage combination therapies to transcend the "incremental effect."

Thus, we see that large pharmaceutical companies, with their money, resources, and experience, can initiate several or even a dozen large-scale Phase III trials simultaneously, exploring multiple indications, treatment lines, and combination regimens. In particular, with the efficacy of PD-1 + ADC being repeatedly validated, the combination of PD-1/VEGF bispecific antibodies is rapidly gaining traction.

BioNTech is advancing clinical trials of BNT327 in combination with three ADCs, covering multiple indications; Pfizer's next plan is to initiate studies of 10 new indications and more than 10 novel combination regimens by the end of 2026. This "saturation" strategy is not only to seize market opportunities, but also to avoid missing out on the overall picture due to the failure of a single indication or combination regimen in the rapidly iterating wave of technology.

This also means that the next generation of the cancer race has been brought to a whole new level.

In addition to the aforementioned factors, another current trend in the oncology field is the combined use of next-generation IO (Initial Imaging Module) and next-generation ADC (Analog-Contractant Module). Akeso Biopharma defines this as "IO + ADC" 2.0.

In July, after the first dose of its first bispecific antibody ADC was administered, Akeso Biopharma divided cancer treatment into four phases: IO + chemotherapy, IO + ADC, IO 2.0 + ADC, and "IO + ADC" 2.0. "IO + ADC" 2.0 refers to iterating PD-1 antibodies to PD-1-related bispecific antibodies and monoclonal antibody ADCs to bispecific antibody ADCs or dual-toxin ADCs.

This strategy goes a step further than IO 2.0 + ADC. However, due to its earlier stage, the effectiveness of its subsequent combined use remains to be seen.

The partnerships between Akeso Biopharma and Yilian Biopharma, and between Kelun Biotech and Crescent, clearly demonstrate that the competition for next-generation combination therapies is not merely a contest of individual assets, but a comprehensive battle of pipeline completeness and collaborative development capabilities. The technological iteration in the oncology field is already rapid, and competitive strategies and landscapes are constantly evolving. This naturally places higher demands on all participants.

Of course, while the PD-1/VEGF bispecific antibody + ADC combination is gaining momentum, the practical challenges in validating its efficacy cannot be ignored. On the one hand, clinical trials are currently in Phase I and II stages, with a long time to go before Phase III. On the other hand, the safety and synergistic effects of the combination therapy need continuous validation. Can the efficacy of the external ADC/bispecific antibody meet expectations, and how well does it match the performance of proprietary assets? These questions require answers based on more clinical data.

https://news.yaozh.com/archive/46444.html