Antibodies for Non-small-cell Lung Cancer

Oncology

We seek to de-risk humanized anti-TIGIT antibodies through in vivo studies with Biocytogen’s transgenic mouse lines. It would be of tremendous interest to further de-risk these antibodies to unlock their values.

Project Team

Eric Goetz
Eric Goetz
Chun-Nan Chen
Chun-Nan Chen

Institutions

AP
Ab Protein
US

Project Status

Clinical Stage
Preclinical
Patent Status
Patent filed

Funding Opportunity

Opportunity type
Funding requested
$1,000,000
Funding allocated
$0

Background

Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indications, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. Toward that end, TIGIT has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells.

Project Details

In cancer contexts, TIGIT is known to be upregulated in tumor-infiltrated T cells. Given that CD155 is highly expressed by both human and mouse tumors and tumor-infiltrating myeloid cells, it has been proposed that TIGIT might inhibit antitumor immune responses via multiple, sequential steps: first, inhibiting NK cell–mediated tumor cell killing as well as tumor Ag release, then inducing tolerogenic dendritic cells and suppressing CD8+ T cell function via TIGIT+ Tregs, and finally directly inhibiting CD8+ T cell effector functions. This sequence of steps may ultimately prevent elimination of cancer cells, so TIGIT is considered to be a key inhibitor in cancer immunity. Targeting TIGIT is viewed as a promising approach for developing cancer immunotherapies. Abs targeting immune checkpoint proteins were initially assumed to modulate the immune activity of effector T cells by blocking their inhibitory function; however, a growing number of studies have reported any such therapeutic effects may actually result from the Fc-mediated effector functions of certain immune modulatory Abs (such as anti–CTLA-4). Abs with different blockade activities could result in similar antitumor efficacy, solely depending on FcγR engagement capability. Anti-TIGIT Abs have shown therapeutic effects in several murine cancer models, and there several Abs now under assessment in human clinical trials. In the proposed study, we wish to demonstrate our newly discovered FaG3 Ab employs multiple mechanisms of action, including blockade of ligand binding, Fc-mediated effector functions that likely result in depletion of intratumoral Tregs via NK cells, and enhancement of CD8+ T cell responses, which collectively contribute to the potent antitumor activity and immune memory effects of this mAb discovered by our flagship technology platform, AbTheneum™.

Project Timeline

  • Demonstrate developability of 3 mAbs

    Required Funding$500,000
    Statusplanned
    Duration6 Months

    One of the key de-risking activities of a therapeutic monoclonal antibody is to demonstrate its developability including manufacturability. Having generated a research cell bank producing a monoclonal antibody with a yield and characteristics usual and customary of the industry standards, the risks of developability is vastly reduced. Process 1. Molecular reconstruction of expression constructs of anti-human mAbs 2. Site-specific knock-in of expression constructs into a production CHO cell line 3. Establishing research cell banks for these mAbs with consistent quality and yield 4. Biophysical characterization of produced mAbs 5. Production of a benchmark anti-human TIGIT mAb currently in a clinical trial 6. Production of a benchmark anti-human PD-1 mAb current on the market

  • In vivo assessment of functional activity of mAbs

    Required Funding$500,000
    Statusplanned
    Duration4 Months

    This phase is to assess the mAbs that were de-risked for developability their functional anti-tumor activity in a genetically engineered mouse strain to circumvent the needs for surrogate anti-mouse mAbs. This innovative genetically engineered mouse strain has the extracellular domain of TIGIT derived from a human molecule but retaining the endogenous mouse intracellular domain for correct signaling. The main objective of the animal studies is to demonstrate synergistic efficacy of our anti-human TIGIT mAb and a benchmark anti-human PD-1 mAb. Once these mAbs demonstrated developability and synergistic functional activity in animals especially against the benchmark mAb combination and proved either on par with or better yet superior with the benchmarks, our mAbs’ values will substantially rise and attract the interest of those interested in pursuing these mAbs in clinical trials thereby resulting in a licensing opportunity for us. Process 1. Administer those anti-human TIGIT mAbs that were sufficiently de-risked in Milestone 1 each into a cohort of 8 CPTB mice implanted with a chosen human tumor cell line 2. Administer the benchmark anti-PD-1 mAb to a cohort of 8 CPTB mice implanted with a chosen human tumor cell line 3. Administer both the anti-human TIGIT mAbs in step 1 under Milestone 2 and the benchmark anti-PD-1 mAb to a cohort of 8 CPTB mice implanted with a chosen human tumor cell line 4. Two additional cohorts are injected with a benchmark mAb, a positive control, and saline solution, a negative control, respectively, for comparison with our anti-human TIGIT mAbs 5. Administer both the benchmark PD-1 mAb and the benchmark anti-human TIGIT mAbs in step 5 under Milestone 2 to a cohort of 8 CPTB mice implanted with a chosen human tumor cell line 6. Monitor these mice for a variety of metrics including tumor size and body weight, for signs of in vivo efficacy