Buried deep within BioAtla's recent earnings call lies a bold strategy, one that has the potential to catapult the company to the forefront of cancer immunotherapy, or leave it lagging behind. This isn't about their promising CAB-ROR2-ADC data in head and neck cancer, which has rightfully garnered attention. It's about something far more daring: their relentless pursuit of pushing the dosage limits of their CAB-CTLA-4 antibody, BA3071, to an unprecedented one gram.

This "one gram gamble," as we'll call it, represents a high-risk, high-reward approach that has largely flown under the radar. While analysts and investors have focused on the positive safety profile and encouraging early efficacy data, few have grasped the true magnitude of BioAtla's ambition. They're not simply aiming for a "better" CTLA-4 inhibitor; they're chasing a paradigm shift in how this powerful class of immunotherapy drugs is used.

To understand the audacity of this strategy, we need to delve into the history of CTLA-4 inhibitors. These drugs work by blocking CTLA-4, a protein that acts as a brake on the immune system, thus unleashing the body's own defenses to attack cancer cells. Ipilimumab (Yervoy), the first approved CTLA-4 inhibitor, demonstrated groundbreaking results in melanoma, but at a steep cost. Its use was marred by a high rate of severe immune-related adverse events, a consequence of its broad immune activation.

This toxicity issue has plagued the entire CTLA-4 inhibitor class, leading to cautious dosing regimens and limiting their widespread adoption. BioAtla, however, believes their CAB technology, which enables the antibody to preferentially bind CTLA-4 in the acidic tumor microenvironment, will circumvent this problem. Their hypothesis: achieve high, unprecedented levels of CTLA-4 blockade in the tumor, while largely avoiding the immune-related side effects that have hampered previous CTLA-4 inhibitors.

Their dose escalation strategy reflects this ambitious goal. After clearing a 700mg dose with tocilizumab for the first two cycles, they're now boldly pushing the envelope with a one gram dose – a staggering 14.2mg/kg based on a 70kg adult. To put this in perspective, the high-dose regimen of ipilimumab, associated with significant toxicity, was only 10mg/kg.

This "go big or go home" approach stems from compelling clinical data suggesting a direct correlation between CTLA-4 inhibition levels and overall survival in metastatic cancers, including melanoma. Early studies showed that higher ipilimumab doses led to significantly improved survival rates, despite increased toxicity. BioAtla is betting that their CAB technology will allow them to unlock this full potential of CTLA-4 blockade, without the associated risks.

The potential rewards are immense. If successful, BA3071 could become the first CTLA-4 inhibitor used as frequently as a PD-1 inhibitor, expanding its applicability across a broad range of solid tumors, both as monotherapy and in combination with other therapies. Imagine a CTLA-4 inhibitor routinely used in first-line settings, alongside PD-1 inhibitors and even in synergy with BioAtla's own CAB-ADC therapies.

But the stakes are high. If the one gram dose proves too toxic, even with the CAB technology, BioAtla's ambition could backfire, potentially setting back the development of BA3071 and casting doubt on the viability of their entire CAB platform.

The data from the ongoing Phase II study, including the unprecedented one gram dose level, is expected later this year. This data readout will be a pivotal moment for BioAtla, potentially validating their "one gram gamble" and opening the doors to a new era of CTLA-4 inhibition, or forcing a reevaluation of their audacious strategy. The eyes of the oncology world will be watching.

Hypothesis and Numbers:

BioAtla's CAB technology will enable them to safely administer a one gram dose (14.2mg/kg) of BA3071, achieving unprecedented levels of CTLA-4 inhibition in the tumor microenvironment, without the severe immune-related adverse events seen with ipilimumab at 10mg/kg.

1 gram (14.2mg/kg) - This represents the unprecedented dose level being evaluated for BA3071.

Ipilimumab (Yervoy) - The first approved CTLA-4 inhibitor, administered at a maximum dose of 10mg/kg.

Success - The one gram dose proves safe and highly effective, validating BioAtla's CAB technology and leading to a paradigm shift in CTLA-4 inhibitor use.

Failure - The one gram dose proves too toxic, even with the CAB technology, potentially hindering the development of BA3071 and raising concerns about the broader applicability of the CAB platform.

Clinical Trial Data: CAB-ROR2-ADC in Head and Neck Cancer

Source: BioAtla Q1 2024 Earnings Call Transcript

Fun Facts

The human body contains about 100 trillion cells. A one gram dose of BA3071 targets a specific protein on immune cells to fight cancer.

The global oncology market is expected to reach over $400 billion by 2027, highlighting the immense need for new and effective cancer therapies.